Izoxazoline derivative and herbicide

ABSTRACT

The present invention aims at providing an isoxazoline derivative and a pharmaceutically acceptable salt thereof, both having an excellent herbicidal effect and an excellent selectivity between crop and weed.  
     The isoxazoline derivative of the present invention is represented by the following general formula:  
                 
 
     wherein R 1  is a haloalkyl group; R 2  is a hydrogen atom, an alkyl group, or the like; R 3 , R 4 , R 5  and R 6  are each a hydrogen atom, or the like; Y is a pyrrolyl group, a pyrazolyl group, an isothiazolyl group, an oxazolyl group, an imidazolyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, a triazolyl group, an oxadiazolyl group, or the like; and n is an integer of 0 to 2.

TECHNICAL FIELD

[0001] The present invention relates to a novel isoxazoline derivativeand a herbicide containing the isoxazoline derivative as an activeingredient.

BACKGROUND ART

[0002] The herbicidal activities of isoxazoline derivatives having ahaloalkyl group at the 5-position of the isoxazoline ring are reportedin, for example, JP-A-8-225548, JP-A-9-328477 and JP-A-9-328483. Thecompound of the present invention, however, is not described in theseliteratures.

[0003] Herbicides applied to useful crops are desired, when applied tosoil or stems and leaves, to show a sufficient herbicidal effect at alow ingredient amount and, moreover, exhibit a high selectivity betweencrop and weed. In these respects, the compounds described in the aboveliteratures are not fully satisfactory.

[0004] In view of the above situation, the present inventors made astudy on the herbicidal effect and selectivity between crop and weed, ofvarious compounds. As a result, the present inventors found out that anovel isoxazoline derivative has an excellent herbicidal effect and anexcellent selectivity between crop and weed. The above finding has ledto the completion of the present invention.

DISCLOSURE OF THE INVENTION

[0005] The present invention provides the followings.

[0006] (1) An isoxazoline derivative having the following generalformula [I] and a pharmaceutically acceptable salt thereof:

[0007] wherein R¹ is a C1 to C4 haloalkyl group;

[0008] R² is a hydrogen atom, a C1 to C10 alkyl group, a C1 to C4haloalkyl group, a C3 to C8 cycloalkyl group, or a C3 to C8 cycloalkylC1 to C3 alkyl group;

[0009] R³ and R⁴ may be the same or different and are each a hydrogenatom, a C1 to C10 alkyl group or a C3 to C8 cycloalkyl group; or R³ andR⁴ may be bonded to each other to form a C3 to C7 spiro ring togetherwith the carbon atom to which they bond; or R² and R³ may be bonded toeach other to form a 5- to 8-membered ring together with the carbonatoms to which they bond;

[0010] R⁵ and R⁶ may be the same or different and are each a hydrogenatom or a C1 to C10 alkyl group;

[0011] Y is a pyrrolyl group, a pyrazolyl group, an isothiazolyl group,an oxazolyl group, an imidazolyl group, a pyridazinyl group, apyrimidinyl group, a pyrazinyl group, a triazinyl group, a triazolylgroup, an oxadiazolyl group, a benzothienyl group, an indolyl group, abenzoxazolyl group, a benzimidazolyl group, a benzoisoxazolyl group, abenzoisothiazolyl group, an indazolyl group, a quinolyl group, anisoquinolyl group, a phthalazinyl group, a quinoxalinyl group, aquinazolinyl group, a cinnolinyl group or a benzotriazolyl group (inthese heterocyclic groups, when the hetero atom is a nitrogen atom, thenitrogen atom may be oxidized to form an N-oxide); these heterocyclicgroups may each be substituted with one to six same or different groupsselected from the following substituent group a (when the heterocyclicgroup is substituted at the two adjacent positions with two alkylgroups, two alkoxy groups, an alkyl group and an alkoxy group, an alkylgroup and an alkylthio group, an alkyl group and an alkylsulfonyl group,an alkyl group and a monoalkylamino group, or an alkyl group and adialkylamino group, the two groups may form a 5- to 8-membered ringwhich may be substituted with 1 to 4 halogen atoms);

[0012] n is an integer of 0 to 2.

SUBSTITUENT GROUP α

[0013] Hydroxyl group; halogen atoms; C1 to C10 alkyl groups; C1 to C10alkyl groups each mono-substituted with a group selected from thefollowing substituent group β, C1 to C4 haloalkyl groups; C3 to C8cycloalkyl groups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups eachmono-substituted with a group selected from the following substituentgroup γ; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3to C8 cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups;C1 to C10 alkylthio groups each mono-substituted with a group selectedfrom the substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6alkenyl groups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2to C6 alkynyloxy groups; C1 to C10 alkylsulfinyl groups; C1 to C10alkylsulfonyl groups; C1 to C10 alkylsulfonyl groups eachmono-substituted with a group selected from the substituent group γ; C1to C4 haloalkylsulfinyl groups; C1 to C4 haloalkylsulfonyl groups; C1 toC10 alkylsulfonyloxy groups; C1 to C4 haloalkylsulfonyloxy groups;optionally substituted phenyl group; optionally substituted phenoxygroup; optionally substituted phenylthio group; optionally substitutedaromatic heterocyclic groups; optionally substituted aromaticheterocyclic oxy groups; optionally substituted aromatic heterocyclicthio groups; optionally substituted phenylsulfinyl groups; optionallysubstituted phenylsulfonyl groups; optionally substituted aromaticheterocyclic sulfinyl groups; optionally substituted aromaticheterocyclic sulfonyl groups; optionally substituted phenylsulfonyloxygroups; C1 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups;optionally substituted benzylcarbonyl group; optionally substitutedbenzoyl group; carboxyl group; C1 to C10 alkoxycarbonyl groups;optionally substituted benzyloxycarbonyl group; optionally substitutedphenoxycarbonyl group; cyano group; carbamoyl group (its nitrogen atommay be substituted with same or different groups selected from C1 to C10alkyl groups and optionally substituted phenyl group); C1 to C6 acyloxygroups; C1 to C4 haloalkylcarbonyloxy groups; optionally substitutedbenzylcarbonyloxy group; optionally substituted benzoyloxy group; nitrogroup; and amino group (its nitrogen atom may be substituted with sameor different groups selected from C1 to C10 alkyl groups, optionallysubstituted phenyl group, C1 to C6 acyl groups, C1 to C4haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group,optionally substituted benzoyl group, C1 to C10 alkylsulfonyl group, C1to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonylgroup, and optionally substituted phenylsulfonyl group).

SUBSTITUENT GROUP β

[0014] Hydroxyl group; C3 to C8 cycloalkyl groups (which may besubstituted with halogen atoms or C1 to C10 alkyl groups); C1 to C10alkoxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylsulfonylgroups; C1 to C10 alkoxycarbonyl groups; C2 to C6 haloalkenyl groups;amino group (its nitrogen atom may be substituted with same or differentgroups selected from C1 to C10 alkyl groups, C2 to C6 acyl groups; C1 toC4 haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4haloalkylsulfonyl groups); carbamoyl group (its nitrogen atom may besubstituted with same or different groups selected from C1 to C10 alkylgroups and optionally substituted phenyl group); C2 to C6 acyl groups;C1 to C4 haloalkylcarbonyl groups; C1 to C10 alkoxyimino groups; cyanogroup; optionally substituted phenyl group; and optionally substitutedphenoxy group.

SUBSTITUENT GROUP γ

[0015] C1 to C10 alkoxycarbonyl groups; optionally substituted phenylgroup; optionally substituted aromatic heterocyclic groups; cyano group;and carbamoyl group (its nitrogen atom may be substituted with same ordifferent C1 to C10 alkyl groups).

[0016] (2) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (1), wherein the substituent group α isrepresented by hydroxyl group; halogen atoms; C1 to C10 alkyl groups; C1to C10 alkyl groups each mono-substituted with a group selected from thesubstituent group β; C1 to C4 haloalkyl groups; C3 to C8 cycloalkylgroups; C1 to C10 alkoxy groups; C1 to C10 alkoxy groups eachmono-substituted with a group selected from the substituent group γ; C1to C4 haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8cycloalkyl C1 to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 toC10 alkylthio groups each mono-substituted with a group selected fromthe substituent group γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenylgroups; C2 to C6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6alkynyloxy groups; C1 to C10 alkylsulfonyl groups; C1 to C4haloalkylsulfonyl groups; optionally substituted phenyl group;optionally substituted phenoxy group; optionally substituted phenylthiogroup; optionally substituted aromatic heterocyclic groups; optionallysubstituted aromatic heterocyclic oxy groups; optionally substitutedaromatic heterocyclic thio groups; optionally substituted phenylsulfonylgroups; optionally substituted aromatic heterocyclic sulfonyl groups; C1to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups; optionallysubstituted benzylcarbonyl group; optionally substituted benzoyl group;carboxyl group; C1 to C10 alkoxycarbonyl groups; cyano group; carbamoylgroup (its nitrogen atom may be substituted with same or differentgroups selected from C1 to C10 alkyl groups and optionally substitutedphenyl group); nitro group; and amino group (its nitrogen atom may besubstituted with same or different groups selected from C1 to C10 alkylgroups, optionally substituted phenyl group, C1 to C6 acyl groups, C1 toC4 haloalkylcarbonyl groups, optionally substituted benzylcarbonylgroup, optionally substituted benzoyl group, C1 to C10 alkylsulfonylgroups, C1 to C4 haloalkylsulfonyl groups, optionally substitutedbenzylsulfonyl group, and optionally substituted phenylsulfonyl group).

[0017] (3) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (2), wherein the substituent group a isrepresented by halogen atoms; C1 to C10 alkyl groups; C1 to C4 haloalkylgroups; C1 to C10 alkoxy C1 to C3 alkyl groups; C3 to C8 cycloalkylgroups (which may be substituted with halogen atom or alkyl group); C1to C10 alkoxy groups; C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyl C1to C3 alkyloxy groups; optionally substituted phenoxy group; C1 to C10alkylthio groups; C1 to C10 alkylsulfonyl groups; acyl groups; C1 to C4haloalkylcarbonyl groups; C1 to C10 alkoxycarbonyl groups; cyano groupand carbamoyl group (its nitrogen atom may be substituted with same ordifferent C1 to C10 alkyl groups).

[0018] (4) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (1), (2) or (3), wherein R¹ is a chloromethylgroup; R² is a methyl group or an ethyl group; R³, R⁴, R⁵ and R⁶ areeach a hydrogen atom.

[0019] (5) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (1), (2), (3) or (4), wherein Y is a pyrrolylgroup, a pyrazolyl group, an isothiazolyl group, an oxazolyl group, animidazolyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinylgroup, a triazinyl group, a triazolyl group or an oxadiazolyl group.

[0020] (6) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (5) , wherein Y is a pyrazolyl group or apyrimidinyl group.

[0021] (7) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (6), wherein Y is a pyrazol-4-yl group or apyrimidin-5-yl group.

[0022] (8) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (7), wherein Y is a pyrazol-4-yl group and thepyrazole ring is substituted at the 3- and 5-positions with a groupselected from the substituent group α and at the 1-position with ahydrogen atom, a C1 to C10 alkyl group, a C1 to C10 alkyl groupmono-substituted with a group selected from the substituent group β, aC1 to C4 haloalkyl group, a C3 to C8 cycloalkyl group, a C2 to C6alkenyl group, a C2 to C6 alkynyl group, a C1 to C10 alkylsulfinylgroup, a C1 to C10 alkylsulfonyl group, a C1 to C10 alkylsulfonyl groupmono-substituted with a group selected from the substituent group γ, aC1 to C4 haloalkylsulfonyl group, an optionally substituted phenylgroup, an optionally substituted aromatic heterocyclic group, anoptionally substituted phenylsulfonyl group, an optionally substitutedaromatic heterocyclic sulfonyl group, an acyl group, a C1 to C4haloalkylcarbonyl group, an optionally substituted benzylcarbonyl group,an optionally substituted benzoyl group, a C1 to C10 alkoxycarbonylgroup, an optionally substituted benzyloxycarbonyl group, an optionallysubstituted phenoxycarbonyl group, a carbamoyl group (its nitrogen atommay be substituted with same or different groups selected from C1 to C10alkyl groups and optionally substituted phenyl group), or an amino group(its nitrogen atom may be substituted with same or different groupsselected from C1 to C10 alkyl groups, optionally substituted phenylgroup, acyl groups, C1 to C4 haloalkylcarbonyl groups, optionallysubstituted benzylcarbonyl group, optionally substituted benzoyl group,C1 to C10 alkylsulfonyl groups, C1 to C4 haloalkylsulfonyl groups,optionally substituted benzylsulfonyl group and optionally substitutedphenylsulfonyl group).

[0023] (9) An isoxazoline derivative or a pharmaceutically acceptablesalt thereof according to (7), wherein Y is a pyrimidin-5-yl group andthe pyrimidine ring are substituted with a group selected from thesubstituent group α, at the 4- and 6-positions.

[0024] (10) A herbicide containing, as an active ingredient, anisoxazoline derivative or a pharmaceutically acceptable salt thereofaccording to any of (1) to (9).

[0025] The definitions of the terms used in the present specificationare given below.

[0026] The expression of “C1 to C10”, etc. indicates that thesubstituent appearing after the expression has 1 to 10 carbon atoms inthe case of “C1 to CO1”.

[0027] Halogen atom refers to a fluorine atom, a chlorine atom, abromine atom or an iodine atom.

[0028] C1 to C10 alkyl group refers, unless otherwise specified, to astraight or branched chain alkyl group of 1 to 10 carbon atoms; andthere can be mentioned, for example, methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, n-pentyl group, isopentyl group, neopentyl group,n-hexyl group, isohexyl group, 3,3-dimethylbutyl group, heptyl group andoctyl group.

[0029] C3 to C8 cycloalkyl group refers to a cycloalkyl group of 3 to 8carbon atoms; and there can be mentioned, for example, cyclopropylgroup, cyclobutyl group, cyclopentyl group and cyclohexyl group.

[0030] C3 to C8 cycloalkyl C1 to C3 alkyl group (which may besubstituted with halogen atom or alkyl group) refers, unless otherwisespecified, to a C1 to C3 alkyl group substituted with a C3 to C8cycloalkyl group which may be substituted with 1 to 4 same or differenthalogen atoms or C1 to C3 alkyl group; and there can be mentioned, forexample, cyclopropylmethyl group, 1-cyclopropylethyl group,2-cyclopropylethyl group, 1-cyclopropylpropyl group, 2-cyclopropylpropylgroup, 3-cyclopropylpropyl group, cyclobutylmethyl group,cyclopentylmethyl group, cyclohexylmethyl group,2-chlorocyclopropylmethyl group, 2,2-dichlorocyclopropylmethyl group,2-fluorocyclopropylmethyl group, 2,2-difluorocyclopropylmethyl group,2-methylcyclopropylmethyl group, 2,2-dimethylcyclopropylmethyl group and2-methylcyclopropylethyl group.

[0031] C3 to C8 cycloalkyl C1 to C3 alkyl group refers to a alkyl groupof 1 to 3 carbon atoms, substituted with a cycloalkyl group of 3 to 8carbon atoms; and there can be mentioned, for example, cyclopropylmethylgroup, 1-cyclopropylethyl group, 2-cyclopropylethyl group,1-cyclopropylpropyl group, 2-cyclopropylpropyl group,3-cyclopropylpropyl group, cyclobutylmethyl group, cyclopentylmethylgroup and cyclohexylmethyl group.

[0032] C1 to C4 haloalkyl group refers, unless otherwise specified, to astraight or branched chain alkyl group of 1 to 4 carbon atoms,substituted with 1 to 9 same or different halogen atoms; and there canbe mentioned, for example, fluoromethyl group, chloromethyl group,bromomethyl group, difluoromethyl group, trifluoromethyl group,2,2-difluoroethyl group, 2,2,2-trifluoroethyl group and pentafluoroethylgroup.

[0033] C2 to C6 alkenyl group refers to a straight or branched chainalkenyl group of 2 to 6 carbon atoms; and there can be mentioned, forexample, ethenyl group, 1-propenyl group, 2-propenyl group, isopropenylgroup, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-pentenylgroup.

[0034] C2 to C6 alkynyl group refers to a straight or branched chainalkynyl group of 2 to 6 carbon atoms; and there can be mentioned, forexample, ethynyl group, 2-propynyl group, 1-methyl-2-propynyl group,2-butynyl group, 3-butynyl group and 2-methyl-3-butynyl group.

[0035] C2 to C6 haloalkenyl group refers, unless otherwise specified, toa straight or branched alkenyl group of 2 to 6 carbon atoms, substitutedwith 1 to 4 same or different halogen atoms; and there can be mentioned,for example, 3-chloro-2-propenyl group and 2-chloro-2-propenyl group.

[0036] C1 to C10 alkoxy group refers to an (alkyl)-O— group wherein thealkyl moiety has the above definition; and there can be mentioned, forexample, methoxy group, ethoxy group, n-propoxy group, isopropoxy group,tert-butoxy group, n-butoxy group, sec-butoxy group and isobutoxy group.

[0037] C1 to C10 alkoxy C1 to C3 alkyl group refers to an(alkyl)-O-(alkyl) group wherein the alkoxy moiety and the alkyl moietyhave the above definitions; and there can be mentioned, for example,methoxymethyl group, ethoxymethyl group, methoxyethyl group andethoxyethyl group.

[0038] C1 to C4 haloalkoxy group refers to a (haloalkyl)-O— groupwherein the haloalkyl moiety has the above definition; and there can bementioned, for example, difluoromethoxy group, trifluoromethoxy group,2,2-difluoroethoxy group and 2,2,2-trifluoroethoxy group.

[0039] C3 to C8 cycloalkyloxy group refers to a (cycloalkyl)-O— groupwherein the cycloalkyl moiety has the above definition; and there can bementioned, for example, cyclopropyloxy group, cyclobutyloxy group,cyclopentyloxy group and cyclohexyloxy group.

[0040] C3 to C8 cycloalkyl C1 to C3 alkyloxy group refers to a(cycloalkylalkyl)-O— group wherein the cycloalkylalkyl moiety has theabove definition; and there can be mentioned, for example,cyclopropylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxygroup, 1-cyclopropylpropoxy group, 2-chclopropylpropoxy group,3-cyclopropylpropoxy group, cyclobutylmethoxy group, cyclopentylmethoxygroup and cyclohexylmethoxy group.

[0041] C2 to C6 alkenyloxy group and C2 to C6 alkynyloxy group refer,respectively, to an (alkenyl)-O— group and an (alkynyl)-O— group, ineach of which the alkenyl or alkynyl moiety has the above definition;and there can be mentioned, for example, 2-propenyloxy group and2-propynyloxy group.

[0042] C1 to C10 alkoxyimino group refers to an (alkoxy)-N═ groupwherein the alkoxy moiety has the above definition; and there can bementioned, for example, methoxyimino group and ethoxyimino group.

[0043] C1 to C10 alkylthio group, C1 to C10 alkylsulfinyl group and C1to C10 alkylsulfonyl group refer, respectively, to an (alkyl)-S— group,an (alkyl)-SO— group and an (alkyl)-SO₂— group, in each of which thealkyl moiety has the above definition; and there can be mentioned, forexample, methylthio group, ethylthio group, n-propylthio group,isopropylthio group, methylsulfinyl group, methylsulfonyl group,ethylsulfonyl group, n-propylsulfonyl group and isopropylsulfonyl group.

[0044] C1 to C10 alkylsulfonyloxy group refers to an (alkylsulfonyl)-O—group wherein the alkylsulfonyl moiety has the above definition, andthere can be mentioned, for example, methylsulfonyloxy group andethylsulfonyloxy group.

[0045] C1 to C10 alkoxycarbonyl group refers to an (alkoxy)-CO— groupwherein the alkoxy moiety has the above definition, and there can bementioned, for example, methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group and isopropoxycarbonyl group.

[0046] C1 to C6 acyl group refers to a straight or branched chainaliphatic acyl group of 1 to 6 carbon atoms, and there can be mentioned,for example, formyl group, acetyl group, propionyl group, isopropionylgroup, butyryl group and pivaloyl group.

[0047] C1 to C10 acyloxy group refers to an (acyl)-O— group wherein theacyl moiety has the above definition; and there can be mentioned, forexample, acetoxy group, propionyloxy group, isopropionyloxy group andpivaloyloxy group.

[0048] C1 to C4 haloalkylcarbonyl group, C1 to C4 haloalkylthio group,C1 to C4 haloalkylsulfinyl group and C1 to C4 haloalkylsulfonyl grouprefers, respectively, to a (haloalkyl)-CO— group, a (haloalkyl)-S—group, a (haloalkyl)-SO— group and a (haloalkyl)-SO₂— group, in each ofwhich the haloalkyl moiety has the above definition; and there can bementioned, for example, chloroacetyl group, trifluoroacetyl group,pentafluoropropionyl group, difluoromethylthio group,trifluoromethylthio group, chloromethylsulfinyl group,difluoromethylsulfinyl group, trifluoromethylsulfinyl group,chloromethylsulfonyl group, difluoromethylsulfonyl group andtrifluoromethylsulfonyl group.

[0049] C1 to C4 haloalkylcarbonyloxy group and C1 to C4haloalkylsulfonyloxy group refer, respectively, to a(haloalkylcarbonyl)-O— group and a (haloalkylsulfonyl)-O— group, in eachof which the haloalkylcarbonyl moiety or the haloalkylsulfonyl moietyhas the above definition; and there can be mentioned, for example,chloroacetyloxy group, trifluoroacetyloxy group, chloromethylsulfonyloxygroup and trifluoromehtylsulfonyloxy group.

[0050] “Optionally substituted” in (optionally substituted) phenylgroup, (optionally substituted) aromatic heterocyclic group, (optionallysubstituted) phenoxy group, (optionally substituted aromaticheterocyclic oxy group, (optionally substituted) phenylthio group,(optionally substituted) aromatic heterocyclic thio group, (optionallysubstituted) phenylsulfinyl group, (optionally substituted)phenylsulfonyl group, (optionally substituted) phenylsulfonyloxy group,(optionally substituted) aromatic heterocyclic sulfinyl group,(optionally substituted) aromatic heterocyclic sulfonyl group,(optionally substituted) benzylcarbonyl group, (optionally substituted)benzylcarbonyloxy group, (optionally substituted) benzylsulfonyl group,(optionally substituted) benzoyl group, (optionally substituted)benzoyloxy group, (optionally substituted) benzyloxycarbonyl group and(optionally substituted) phenoxycarbonyl group, refers to beingoptionally substituted with, for example, halogen atom, C1 to C10 alkylgroup, C1 to C4 haloalkyl group, C1 to C10 alkoxy C1 to C3 alkyl group,C1 to C10 alkoxy group, C1 to C10 alkylthio group, C1 to C10alkylsulfonyl group, acyl group, C1 to C10 alkoxycarbonyl group, cyanogroup, carbamoyl group (its nitrogen atom may be substituted with sameor different C1 to C10 alkyl groups), nitro group, or amino group (itsnitrogen atom may be substituted with same or different groups selectedfrom C1 to C10 alkyl groups, C1 to C6 acyl groups, C1 to C4haloalkylcarbonyl groups, C1 to C10 alkylsulfonyl groups and C1 to C4haloalkylsulfonyl groups).

[0051] Aromatic heterocycle in (optionally substituted) aromaticheterocyclic group, (optionally substituted) aromatic heterocyclic oxygroup, (optionally substituted) aromatic heterocyclic thio group,(optionally substituted) aromatic heterocyclic sulfinyl group and(optionally substituted) aromatic heterocyclic sulfonyl group, refers toa 5- to 6-membered group having 1 to 3 hetero atoms randomly selectedfrom nitrogen atom, oxygen atom and sulfur atom; and there can bementioned, for example, furyl group, thienyl group, pyrrolyl group,pyrazolyl group, isoxazolyl group, isothiazolyl group, oxazolyl group,thiazolyl group, imidazolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, triazinyl group, triazolyl group,oxadiazolyl group and thiadiazolyl group.

[0052] Pharmaceutically acceptable salt is a salt of a compound of thegeneral formula [I] having, in the structure, hydroxyl group, carboxylgroup, amino group or the like, with a metal or an organic base or witha mineral acid or an organic acid. As the metal, there can be mentionedalkali metals such as sodium, potassium and the like; and alkaline earthmetals such as magnesium, calcium and the like. As the organic base,there can be mentioned triethylamine, diisopropylamine, etc. As themineral acid, there can be mentioned hydrochloric acid, sulfuric acid,etc. As the organic acid, there can be mentioned acetic acid,methanesulfonic acid, p-toluenesulfonic acid, etc.

[0053] Of the compounds represented by the general formula [I],preferred is an isoxazoline derivative wherein

[0054] R¹ is a chloromethyl group;

[0055] R²is a methyl group or an ethyl group;

[0056] R³, R⁴, R⁵ and R⁶ are each a hydrogen atom;

[0057] n is an integer of 2; and

[0058] Y is a pyrazol-4-yl group which is substituted, at the 3- and5-positions, with halogen atom, alkyl group, haloalkyl group,alkoxyalkyl group, cycloalkyl group, alkoxy group, haloalkoxy group,cycloalkylalkyloxy group, optionally substituted phenoxy group,alkylthio group, alkylsulfonyl group, acyl group, haloalkylcarbonylgroup, alkoxycarbonyl group, cyano group or carbamoyl group (itsnitrogen atom may be substituted with same or different alkyl groups)and, at the 1-position, with hydrogen atom, alkyl group, alkyl groupmono-substituted with a group selected from the substituent group β,haloalkyl group, cycloalkyl group, alkenyl group, alkynyl group,alkylsulfonyl group, alkylsulfonyl group mono-substituted with a groupselected from the substituent group γ, haloalkylsulfonyl group,optionally substituted phenyl group, optionally substituted aromaticheterocyclic group, optionally substituted phenylsulfonyl group,optionally substituted aromatic heterosulfonyl group, acyl group,haloalkylcarbonyl group, optionally substituted benzylcarbonyl group,optionally substituted benzoyl group, alkoxycarbonyl group, optionallysubstituted benzoyloxycarbonyl group, optionally substitutedphenoxycarbonyl group or carbamoyl group (its nitrogen atom may besubstituted with same or different alkyl groups or optionallysubstituted phenyl group); or Y is a pyrimidin-5-yl group which issubstituted, at the 4- and 6-positions, with halogen atom, alkyl group,haloalkyl group, alkoxyalkyl group, cycloalkyl group, alkoxy group,haloalkoxy group, alkylthio group, alkylsulfonyl group, acyl group,haloalkylcarbonyl group, alkoxycarbonyl group, cyano group or carbamoylgroup (its nitrogen atom may be substituted with same or different alkylgroups).

BEST MODE FOR CARRYING OUT THE INVENTION

[0059] Next, representative examples of the present compound representedby the general formula [I] are shown in Tables 1 to 57. However, thepresent compound is not restricted to these examples.

[0060] The following abbreviated expressions used in the Tables of thepresent invention refer to the following groups. Me: methyl group Et:ethyl group Pr: n-propyl group Pr-i: isopropyl group Pr-c: cyclopropylgroup Bu: n-butyl group Bu-i: isobutyl group Bu-sec: sec-butyl groupBu-t: tert-butyl group Bu-c: cyclobutyl group Pen-c: cyclopentyl groupHex-c: cyclohexyl group Ph: phenyl group

[0061] When the present compound of the general formula [I] containshydroxyl group as a substituent, there may exist keto-enol tautomers.Any of these tautomers and any mixture of these tautomers are includedin the present compound. TABLE 1

R¹ R² R³ R⁴ n R⁵ R⁶ Z¹ R¹² R¹³ R¹⁴ CH₂Cl Me H H 2 H H N-Me Me H Me CH₂ClMe H H 2 H H N-Me Me C(═O)OMe CH₂C(═O)OMe CH₂Cl Me H H 2 H H N-Me MeC(═O)OEt CH₂C(═O)OEt CH₂Cl Me H H 2 H H N-Me Me Me Me CH₂Cl Me H H 2 H HN-Ph OMe H H CH₂Cl Me H H 2 H H N-Ph OEt H H CH₂Cl Me H H 2 H H N-PhOCHF₂ H H CH₂Cl Me H H 1 H H N-Me Me H Me CH₂Cl Me H H 1 H H N-Me MeC(═O)OMe CH₂C(═O)OMe CH₂Cl Me H H 1 H H N-Me Me C(═O)OEt CH₂C(═O)OEtCH₂Cl Me H H 1 H H N-Me Me Me Me CH₂Cl Me H H 1 H H N-Ph OMe H H CH₂ClMe H H 1 H H N-Ph OEt H H CH₂Cl Me H H 1 H H N-Ph OCHF₂ H H CH₂Cl Me H H0 H H N-Me Me H Me CH₂Cl Me H H 0 H H N-Me Me C(═O)OMe CH₂C(═O)OMe CH₂ClMe H H 0 H H N-Me Me C(═O)OEt CH₂C(═O)OEt CH₂Cl Me H H 0 H H N-Me Me MeMe CH₂Cl Me H H 0 H H N-Ph OMe H H CH₂Cl Me H H 0 H H N-Ph OEt H H CH₂ClMe H H 0 H H N-Ph OCHF₂ H H CH₂Cl Et H H 2 H H N-H H H H

[0062] TABLE 2

R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H H N-Me Cl CH₂Cl Me H H2 H H Me N-Me Me CH₂Cl Me H H 2 H H Me N-Me Cl CH₂Cl Me H H 2 H H ClN-Me Cl CH₂Cl Me H H 2 H H Cl N-Me CF₃ CH₂Cl Me H H 2 H H CHF₂ N-Me ClCH₂Cl Me H H 2 H H CF₃ N-Me Cl CH₂Cl Me H H 2 H H CF₃ N-Me CN CH₂Cl Me HH 2 H H CF₃ N-Me OMe CH₂Cl Me H H 2 H H CF₃ N-Me OEt CH₂Cl Me H H 2 H HCF₃ N-Me OPr-i CH₂Cl Me H H 2 H H CF₃ N-Me OPr CH₂Cl Me H H 2 H H CF₃N-Me OCH₂CH═CH₂ CH₂Cl Me H H 2 H H CF₃ N-Me OCH₂CF₃ CH₂Cl Me H H 2 H HCF₃ N-Me OPh CH₂Cl Me H H 2 H H CF₃ N-Me SMe CH₂Cl Me H H 2 H H CF₃ N-MeSOMe CH₂Cl Me H H 2 H H CF₃ N-Me SO₂Me CH₂Cl Me H H 2 H H CF₃ N-Me SCF₃CH₂Cl Me H H 2 H H CF₃ N-Me SOCF₃ CH₂Cl Me H H 2 H H CF₃ N-Me SO₂CF₃CH₂Cl Me H H 2 H H CF₃ N-Me SPh CH₂Cl Me H H 2 H H CF₃ N-Me SOPh CH₂ClMe H H 2 H H CF₃ N-Me SO₂Ph CH₂Cl Me H H 2 H H CF₃ N-Me Ph CH₂Cl Me H H2 H H CF₂CF₃ N-Me Cl CH₂Cl Me H H 2 H H CF₃ N-H Cl CH₂Cl Me H H 2 H HCF₃ N-CH₂OH Cl CH₂Cl Me H H 2 H H CF₃ N-CH₂OMe Cl CH₂Cl Me H H 2 H H CF₃N-CH₂CN Cl

[0063] TABLE 3 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N—CH₂CH═CH₂ Cl CH₂Cl Me H H 2 H H CF₃ N—CH₂C≡CH Cl CH₂Cl Me H H 2 H HCF₃ N-Et Cl CH₂Cl Me H H 2 H H CF₃ N-Pr-i Cl CH₂Cl Me H H 2 H H CF₃ N-PrCl CH₂Cl Me H H 2 H H CF₃ N-Bu-t Cl CH₂Cl Me H H 2 H H CF₃ N—CH₂Ph ClCH₂Cl Me H H 2 H H CF₃ N—CH₂CF₃ Cl CH₂Cl Me H H 2 H H CF₃ N—CH₂C(═O)OMeCl CH₂Cl Me H H 2 H H CF₃ N—CH(Me)C(═O)OMe Cl CH₂Cl Me H H 2 H H CF₃N—C(Me)₂C(═O)OMe Cl CH₂Cl Me H H 2 H H CF₃ N—CH₂CH₂SMe Cl CH₂Cl Me H H 2H H CF₃ N—CH₂CH₂SO₂Me Cl CH₂Cl Me H H 2 H H CF₃ N—SO₂Me Cl CH₂Cl Me H H2 H H CF₃ NSO₂CHF₂ Cl CH₂Cl Me H H 2 H H CF₃ NSO₂CF₃ Cl CH₂Cl Me H H 2 HH CF₃ NSO₂Ph Cl CH₂Cl Me H H 2 H H CF₃ N—C(═O)Me Cl CH₂Cl Me H H 2 H HCF₃ N—C(═O)Ph Cl CH₂Cl Me H H 2 H H CF₃ N—C(═O)CH₂Ph Cl CH₂Cl Me H H 2 HH Me N-Ph Me CH₂Cl Me H H 2 H H Et N-Ph Cl CH₂Cl Me H H 2 H H Pr N-Ph ClCH₂Cl Me H H 2 H H Pr-i N-Ph Cl CH₂Cl Me H H 2 H H Bu-t N-Ph Cl CH₂Cl MeH H 2 H H CH₂OMe N-Ph Cl CH₂Cl Me H H 2 H H CF₃ N-Ph Me CH₂Cl Me H H 2 HH CH_(F2) N-Ph Cl CH₂Cl Me H H 2 H H CF₃ N-Ph Cl CH₂Cl Me H H 2 H H CF₃N-Ph OMe CH₂Cl Me H H 2 H H CF₃ N-Ph OEt CH₂Cl Me H H 2 H H CF₃ N-PhOPr-i CH₂Cl Me H H 2 H H CF₃ N-Ph OCH₂CH═CH₂ CH₂Cl Me H H 2 H H CF₃ N-PhOCH₂C≡CH CH₂Cl Me H H 2 H H CF₃ N-Ph OCH₂CF₃

[0064] TABLE 4 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N-Ph OCH₂C(═O)OMe CH₂Cl Me H H 2 H H CF₃ N-Ph OCH(Me)C(═O)OMe CH₂Cl Me HH 2 H H CF₃ N-Ph OC(Me)₂C(═O)OMe CH₂Cl Me H H 2 H H CF₃ N-Ph OH CH₂Cl MeH H 2 H H CF₃ N-Ph OC(═O)Me CH₂Cl Me H H 2 H H CF₃ N-Ph OC(═O)Ph CH₂ClMe H H 2 H H CF₃ N-Ph OSO₂Me CH₂Cl Me H H 2 H H CF₃ N-Ph OSO₂CF₃ CH₂ClMe H H 2 H H CF₃ N-Ph OSO₂Ph CH₂Cl Me H H 2 H H CF₃ N-Ph SMe CH₂Cl Me HH 2 H H CF₃ N-Ph SOMe CH₂Cl Me H H 2 H H CF₃ N-Ph SO₂Me CH₂Cl Me H H 2 HH CF₃ N-Ph SPh CH₂Cl Me H H 2 H H CF₃ N-Ph SOPh CH₂Cl Me H H 2 H H CF₃N-Ph SO₂Ph CH₂Cl Me H H 2 H H CF₃ N-Ph Imidazol-1-yl CH₂Cl Me H H 2 H HCF₃ N-Ph 1,2,4-Triazol-1-yl CH₂Cl Me H H 2 H H CF₃ N-Ph1,2,4-Triazol-4-yl CH₂Cl Me H H 2 H H CF₃ N-Ph Tetrazol-1-yl CH₂Cl Me HH 2 H H CF₂CF₃ N-Ph Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(2—Cl) Cl CH₂Cl Me H H2 H H CF₃ N-Ph(2—F) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(2—OMe) Cl CH₂Cl Me HH 2 H H CF₃ N-Ph(2—Me) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(2—NO₂) Cl CH₂Cl MeH H 2 H H CF₃ N-Ph(3—Cl) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(3—F) Cl CH₂Cl MeH H 2 H H CF₃ N-Ph(3—OMe) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(3—Me) Cl CH₂ClMe H H 2 H H CF₃ N-Ph(3—NO₂) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(4—Cl) ClCH₂Cl Me H H 2 H H CF₃ N-Ph(4—F) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(4—OMe)Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(4—Me) Cl CH₂Cl Me H H 2 H H CF₃N-Ph(4—NO₂) Cl

[0065] TABLE 5 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H Ph N-MeMe CH₂Cl Me H H 2 H H Ph N-Me Cl CH₂Cl Me H H 2 H H Ph N-Me OEt CH₂Cl MeH H 2 H H Ph N-Me CF₃ CH₂Cl Me H H 2 H H Ph N-Me Ph CH₂Cl Me H H 2 H HMe S Cl CH₂Cl Me H H 2 H H Me S OEt CH₂Cl Me H H 2 H H CF₃ S Cl CH₂Cl MeH H 2 H H CF₃ S OMe CH₂Cl Me H H 2 H H CF₃ S OEt CH₂Br H H H 2 H H CF₃N-Me Cl CH₂Cl H H H 2 H H CF₃ N-Me Cl CH₂Cl H Me H 2 H H CF₃ N-Me ClCH₂Cl Me H H 2 Me H CF₃ N-Me Cl CH₂Cl Me H H 2 Et H CF₃ N-Me Cl CH₂Cl MeH H 2 Pr-i H CF₃ N-Me Cl CH₂Cl Me H H 2 Me Me CF₃ N-Me Cl CH₂Cl Et H H 2H H CF₃ N-Me Cl CH₂Cl CH₂Cl H H 2 H H CF₃ N-Me Cl CH₂Cl Pr-i H H 2 H HCF₃ N-Me Cl CH₂Cl Pr H H 2 H H CF₃ N-Me Cl CH₂Cl Pr-c H H 2 H H CF₃ N-MeCl CH₂Cl CH₂Pr-c H H 2 H H CF₃ N-Me Cl CH₂F Me H H 2 H H CF₃ N-Me ClCH₂Br Me H H 2 H H CF₃ N-Me Cl CH₂I Me H H 2 H H CF₃ N-Me Cl CF₃ Me H H2 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₃— H 2 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₄— H 2H H CF₃ N-Me Cl CH₂Cl —(CH₂)₅— H 2 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₆— H 2 HH CF₃ N-Me Cl CH₂Cl Me H H 1 H H H N-Me Cl CH₂Cl Me H H 1 H H Me N-Me MeCH₂Cl Me H H 1 H H Me N-Me Cl CH₂Cl Me H H 1 H H Cl N-Me Cl

[0066] TABLE 6 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H Cl N-MeCF₃ CH₂Cl Me H H 1 H H CHF₂ N-Me Cl CH₂Cl Me H H 1 H H CF₃ N-Me Cl CH₂ClMe H H 1 H H CF₃ N-Me CN CH₂Cl Me H H 1 H H CF₃ N-Me OMe CH₂Cl Me H H 1H H CF₃ N-Me OEt CH₂Cl Me H H 1 H H CF₃ N-Me OPr-i CH₂Cl Me H H 1 H HCF₃ N-Me OPr CH₂Cl Me H H 1 H H CF₃ N-Me OCH₂CH═CH₂ CH₂Cl Me H H 1 H HCF₃ N-Me OCH₂CF₃ CH₂Cl Me H H 1 H H CF₃ N-Me OPh CH₂Cl Me H H 1 H H CF₃N-Me SMe CH₂Cl Me H H 1 H H CF₃ N-Me SOMe CH₂Cl Me H H 1 H H CF₃ N-MeSO₂Me CH₂Cl Me H H 1 H H CF₃ N-Me SCF₃ CH₂Cl Me H H 1 H H CF₃ N-Me SOCF₃CH₂Cl Me H H 1 H H CF₃ N-Me SO₂CF₃ CH₂Cl Me H H 1 H H CF₃ N-Me SPh CH₂ClMe H H 1 H H CF₃ N-Me SOPh CH₂Cl Me H H 1 H H CF₃ N-Me SO₂Ph CH₂Cl Me HH 1 H H CF₃ N-Me Ph CH₂Cl Me H H 1 H H CF₂CF₃ N-Me Cl CH₂Cl Me H H 1 H HCF₃ N-Me Cl CH₂Cl Me H H 1 H H CF₃ N-CH₂OH Cl CH₂Cl Me H H 1 H H CF₃N-CH₂OMe Cl CH₂Cl Me H H 1 H H CF₃ N-CH₂CN Cl CH₂Cl Me H H 1 H H CF₃N-CH₂CH═CH₂ Cl CH₂Cl Me H H 1 H H CF₃ N-CH₂C≡CH Cl CH₂Cl Me H H 1 H HCF₃ N-Et Cl CH₂Cl Me H H 1 H H CF₃ N-Pr-i Cl CH₂Cl Me H H 1 H H CF₃ N-PrCl CH₂Cl Me H H 1 H H CF₃ N-Bu-t Cl CH₂Cl Me H H 1 H H CF₃ N—CH₂Ph ClCH₂Cl Me H H 1 H H CF₃ N—CH₂CF₃ Cl CH₂Cl Me H H 1 H H CF₃ N—CH₂C(═O)OMeCl

[0067] TABLE 7 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H CF₃N—CH(Me)C(═O)OMe Cl CH₂Cl Me H H 1 H H CF₃ N—C(Me)₂C(═O)OMe Cl CH₂Cl MeH H 1 H H CF₃ N—CH₂CH₂SMe Cl CH₂Cl Me H H 1 H H CF₃ N—CH₃CH₂SO₂Me ClCH₂Cl Me H H 1 H H CF₃ N—SO₂Me Cl CH₂Cl Me H H 1 H H CF₃ N—SO₂CHF₂ ClCH₂Cl Me H H 1 H H CF₃ N—SO₂CF₃ Cl CH₂Cl Me H H 1 H H CF₃ N—SO₂Ph ClCH₂Cl Me H H 1 H H CF₃ N—C(═O)Me Cl CH₂Cl Me H H 1 H H CF₃ N—C(═O)Ph ClCH₂Cl Me H H 1 H H CF₃ N—C(═O)CH₂Ph Cl CH₂Cl Me H H 1 H H Me N-Ph MeCH₂Cl Me H H 1 H H Me N-Ph Cl CH₂Cl Me H H 1 H H Et N-Ph Cl CH₂Cl Me H H1 H H Pr N-Ph Cl CH₂Cl Me H H 1 H H Pr-i N-Ph Cl CH₂Cl Me H H 1 H H Bu-tN-Ph Cl CH₂Cl Me H H 1 H H CH₂OMe N-Ph Cl CH₂Cl Me H H 1 H H CF₃ N-Ph MeCH₂Cl Me H H 1 H H CHF₂ N-Ph Cl CH₂Cl Me H H 1 H H CF₃ N-Ph Cl CH₂Cl MeH H 1 H H CF₃ N-Ph OMe CH₂Cl Me H H 1 H H CF₃ N-Ph OEt CH₂Cl Me H H 1 HH CF₃ N-Ph OPr-i CH₂Cl Me H H 1 H H CF₃ N-Ph OCH₂CH═CH₂ CH₂Cl Me H H 1 HH CF₃ N-Ph OCH₂C≡CH CH₂Cl Me H H 1 H H CF₃ N-Ph OCH₂CF₃ CH₂Cl Me H H 1 HH CF₃ N-Ph OCH₂C(═O)OMe CH₂Cl Me H H 1 H H CF₃ N-Ph OCH(Me)C(═O)OMeCH₂Cl Me H H 1 H H CF₃ N-Ph OC(Me)₂C(═O)OMe CH₂Cl Me H H 1 H H CF₃ N-PhOH CH₂Cl Me H H 1 H H CF₃ N-Ph OC(═O)Me CH₂Cl Me H H 1 H H CF₃ N-PhOC(═O)Ph CH₂Cl Me H H 1 H H CF₃ N-Ph OSO₂Me CH₂Cl Me H H 1 H H CF₃ N-PhOSO₂CF₃

[0068] TABLE 8 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H CF₃N-Ph OSO₂Ph CH₂Cl Me H H 1 H H CF₃ N-Ph SMe CH₂Cl Me H H 1 H H CF₃ N-PhSOMe CH₂Cl Me H H 1 H H CF₃ N-Ph SO₂Me CH₂Cl Me H H 1 H H CF₃ N-Ph SPhCH₂Cl Me H H 1 H H CF₃ N-Ph SOPh CH₂Cl Me H H 1 H H CF₃ N-Ph SO₂Ph CH₂ClMe H H 1 H H CF₃ N-Ph Imidazol-1-yl CH₂Cl Me H H 1 H H CF₃ N-Ph1,2,4-Triazol-1-yl CH₂Cl Me H H 1 H H CF₃ N-Ph 1,2,4-Triazol-4-yl CH₂ClMe H H 1 H H CF₃ N -Ph Tetrazol-1-yl CH₂Cl Me H H 1 H H CF₂CF₃ N-Ph ClCH₂Cl Me H H 1 H H CF₃ N-Ph(2—Cl) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(2—F) ClCH₂Cl Me H H 1 H H CF₃ N-Ph(2—OMe) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(2—Me)Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(2—NO₂) Cl CH₂Cl Me H H 1 H H CF₃N-Ph(3—Cl) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(3—F) Cl CH₂Cl Me H H 1 H H CF₃N-Ph(3—OMe) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(3-Me) Cl CH₂Cl Me H H 1 H HCF₃ N-Ph(3—NO₂) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(4—Cl) Cl CH₂Cl Me H H 1 HH CF₃ N-Ph(4—F) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(4—OMe) Cl CH₂Cl Me H H 1H H CF₃ N-Ph(4-Me) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(4—NO₂) Cl CH₂Cl Me H H1 H H Ph N-Me Me CH₂Cl Me H H 1 H H Ph N-Me Cl CH₂Cl Me H H 1 H H PhN-Me OEt CH₂Cl Me H H 1 H H Ph N-Me CF₃ CH₂Cl Me H H 1 H H Ph N-Me PhCH₂Cl Me H H 1 H H Me S Cl CH₂Cl Me H H 1 H H Me S OEt CH₂Cl Me H H 1 HH CF₃ S Cl

[0069] TABLE 9 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H CF₃ SOMe CH₂Cl Me H H 1 H H CF₃ S OEt CH₂Cl H H H 1 H H CF₃ N-Me Cl CH₂Cl H HH 1 H H CF₃ N-Me Cl CH₂Cl H Me H 1 H H CF₃ N-Me Cl CH₂Cl Me H H 1 Me HCF₃ N-Me Cl CH₂Cl Me H H 1 Et H CF₃ N-Me Cl CH₂Cl Me H H 1 Pr-i H CF₃N-Me Cl CH₂Cl Me H H 1 Me Me CF₃ N-Me Cl CH₂Cl Et H H 1 H H CF₃ N-Me ClCH₂Cl CH₂Cl H H 1 H H CF₃ N-Me Cl CH₂Cl Pr-i H H 1 H H CF₃ N-Me Cl CH₂ClPr H H 1 H H CF₃ N-Me Cl CH₂Cl Pr-c H H 1 H H CF₃ N-Me Cl CH₂Cl CH₂Pr-cH H 1 H H CF₃ N-Me Cl CH₂F Me H H 1 H H CF₃ N-Me Cl CH₂Br Me H H 1 H HCF₃ N-Me Cl CH₂I Me H H 1 H H CF₃ N-Me Cl CF₃ Me H H 1 H H CF₃ N-Me ClCH₂Cl —(CH₂)₃— H 1 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₄— H 1 H H CF₃ N-Me ClCH₂Cl —(CH₂)₅— H 1 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₆— H 1 H H CF₃ N-Me ClCH₂Cl Me H H 0 H H H N-Me Cl CH₂Cl Me H H 0 H H Me N-Me Me CH₂Cl Me H H0 H H Me N-Me Cl CH₂Cl Me H H 0 H H Cl N-Me Cl CH₂Cl Me H H 0 H H ClN-Me CF₃ CH₂Cl Me H H 0 H H CHF₂ N-Me Cl CH₂Cl Me H H 0 H H CF₃ N-Me ClCH₂Cl Me H H 0 H H CF₃ N-Me CN CH₂Cl Me H H 0 H H CF₃ N-Me OMe CH₂Cl MeH H 0 H H CF₃ N-Me OEt CH₂Cl Me H H 0 H H CF₃ N-Me OPr-i CH₂Cl Me H H 0H H CF₃ N-Me OPr

[0070] TABLE 10 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N-Me OCH₂CH═CH₂ CH₂Cl Me H H 0 H H CF₃ N-Me OCH₂CF₃ CH₂Cl Me H H 0 H HCF₃ N-Me OPh CH₂Cl Me H H 0 H H CF₃ N-Me SMe CH₂Cl Me H H 0 H H CF₃ N-MeSOMe CH₂Cl Me H H 0 H H CF₃ N-Me SO₂Me CH₂Cl Me H H 0 H H CF₃ N-Me SCF₃CH₂Cl Me H H 0 H H CF₃ N-Me SOCF₃ CH₂Cl Me H H 0 H H CF₃ N-Me SO₂CF₃CH₂Cl Me H H 0 H H CF₃ N-Me SPh CH₂Cl Me H H 0 H H CF₃ N-Me SOPh CH₂ClMe H H 0 H H CF₃ N-Me SO₂Ph CH₂Cl Me H H 0 H H CF₃ N-Me Ph CH₂Cl Me H H0 H H CF₂CF₃ N-Me Cl CH₂Cl Me H H 0 H H CF₃ N-Me Cl CH₂Cl Me H H 0 H HCF₃ N—CH₂OH Cl CH₂Cl Me H H 0 H H CF₃ N—CH₂OMe Cl CH₂Cl Me H H 0 H H CF₃N—CH₂CN Cl CH₂Cl Me H H 0 H H CF₃ N—CH₂CH═CH₂ Cl CH₂Cl Me H H 0 H H CF₃N—CH₂C≡CH Cl CH₂Cl Me H H 0 H H CF₃ N-Et Cl CH₂Cl Me H H 0 H H CF₃N-Pr-i Cl CH₂Cl Me H H 0 H H CF₃ N-Pr Cl CH₂Cl Me H H 0 H H CF₃ N-Bu-tCl CH₂Cl Me H H 0 H H CF₃ N—CH₂Ph Cl CH₂Cl Me H H 0 H H CF₃ N—CH₂CF₃ ClCH₂Cl Me H H 0 H H CF₃ N—CH₂C(═O)OMe Cl CH₂Cl Me H H 0 H H CF₃N—CH(Me)C(═O)OMe Cl CH₂Cl Me H H 0 H H CF₃ N—C(Me)₂C(═O)OMe Cl CH₂Cl MeH H 0 H H CF₃ N—CH₂CH₂SMe Cl CH₂Cl Me H H 0 H H CF₃ N—CH₂CH₂SO₂Me ClCH₂Cl Me H H 0 H H CF₃ N—SO₂Me Cl CH₂Cl Me H H 0 H H CF₃ N—SO₂CHF₂ ClCH₂Cl Me H H 0 H H CF₃ N—SO₂CF₃ Cl CH₂Cl Me H H 0 H H CF₃ N—SO₂Ph Cl

[0071] TABLE 11 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N—C(═O)Me Cl CH₂Cl Me H H 0 H H CF₃ N—C(═O)Ph Cl CH₂Cl Me H H 0 H H CF₃N—C(═O)CH₂Ph Cl CH₂Cl Me H H 0 H H Me N-Ph Me CH₂Cl Me H H 0 H H Me N-PhCl CH₂Cl Me H H 0 H H Et N-Ph Cl CH₂Cl Me H H 0 H H Pr N-Ph Cl CH₂Cl MeH H 0 H H Pr-i N-Ph Cl CH₂Cl Me H H 0 H H Bu-t N-Ph Cl CH₂Cl Me H H 0 HH CH₂OMe N-Ph Cl CH₂Cl Me H H 0 H H CF₃ N-Ph Me CH₂Cl Me H H 0 H H CHF₂N-Ph Cl CH₂Cl Me H H 0 H H CF₃ N-Ph Cl CH₂Cl Me H H 0 H H CF₃ N-Ph OMeCH₂Cl Me H H 0 H H CF₃ N-Ph OEt CH₂Cl Me H H 0 H H CF₃ N-Ph OPr-i CH₂ClMe H H 0 H H CF₃ N-Ph OCH₂CH═CH₂ CH₂Cl Me H H 0 H H CF₃ N-Ph OCH₂C≡CHCH₂Cl Me H H 0 H H CF₃ N-Ph OCH₂CF₃ CH₂Cl Me H H 0 H H CF₃ N-PhOCH₂C(═O)OMe CH₂Cl Me H H 0 H H CF₃ N-Ph OCH(Me)C(═O)OMe CH₂Cl Me H H 0H H CF₃ N-Ph OC(Me)₂C(═O)OMe CH₂Cl Me H H 0 H H CF₃ N-Ph OH CH₂Cl Me H H0 H H CF₃ N-Ph OC(═O)Me CH₂Cl Me H H 0 H H CF₃ N-Ph OC(═O)Ph CH₂Cl Me HH 0 H H CF₃ N-Ph OSO₂Me CH₂Cl Me H H 0 H H CF₃ N-Ph OSO₂CF₃ CH₂Cl Me H H0 H H CF₃ N-Ph OSO₂Ph CH₂Cl Me H H 0 H H CF₃ N-Ph SMe CH₂Cl Me H H 0 H HCF₃ N-Ph SOMe CH₂Cl Me H H 0 H H CF₃ N-Ph SO₂Me CH₂Cl Me H H 0 H H CF₃N-Ph SPh CH₂Cl Me H H 0 H H CF₃ N-Ph SOPh CH₂Cl Me H H 0 H H CF₃ N-PhSO₂Ph CH₂Cl Me H H 0 H H CF₃ N-Ph Imidazol-1-yl

[0072] TABLE 12 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N-Ph 1,2,4-Triazol-1-yl CH₂Cl Me H H 0 H H CF₃ N-Ph 1,2,4-Triazol-4-ylCH₂Cl Me H H 0 H H CF₃ N-Ph Tetrazol-1-yl CH₂Cl Me H H 0 H H CF₂CF₃ N-PhCl CH₂Cl Me H H 0 H H CF₃ N-Ph(2—Cl) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(2—F)Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(2—OMe) Cl CH₂Cl Me H H 0 H H CF₃N-Ph(2-Me) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(2—NO₂) Cl CH₂Cl Me H H 0 H HCF₃ N-Ph(3—Cl) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(3—F) Cl CH₂Cl Me H H 0 H HCF₃ N-Ph(3—OMe) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(3-Me) Cl CH₂Cl Me H H 0 HH CF₃ N-Ph(3—NO₂) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(4—Cl) Cl CH₂Cl Me H H 0H H CF₃ N-Ph(4—F) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(4—OMe) Cl CH₂Cl Me H H0 H H CF₃ N-Ph(4-Me) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(4—NO₂) Cl CH₂Cl Me HH 0 H H Ph N-Me Me CH₂Cl Me H H 0 H H Ph N-Me Cl CH₂Cl Me H H 0 H H PhN-Me OEt CH₂Cl Me H H 0 H H Ph N-Me CF₃ CH₂Cl Me H H 0 H H Ph N-Me PhCH₂Cl Me H H 0 H H Me S Cl CH₂Cl Me H H 0 H H Me S OEt CH₂Cl Me H H 0 HH CF₃ S Cl CH₂Cl Me H H 0 H H CF₃ S OMe CH₂Cl Me H H 0 H H CF₃ S OEtCH₂Cl H H H 0 H H CF₃ N-Me Cl CH₂Cl H H H 0 H H CF₃ N-Me Cl CH₂Cl H Me H0 H H CF₃ N-Me Cl CH₂Cl Me H H 0 Me H CF₃ N-Me Cl CH₂Cl Me H H 0 Et HCF₃ N-Me Cl CH₂Cl Me H H 0 Pr-i H CF₃ N-Me Cl

[0073] TABLE 13 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 Me Me CF₃N-Me Cl CH₂Cl Et H H 0 H H CF₃ N-Me Cl CH₂Cl CH₂Cl H H 0 H H CF₃ N-Me ClCH₂Cl Pr-i H H 0 H H CF₃ N-Me Cl CH₂Cl Pr H H 0 H H CF₃ N-Me Cl CH₂ClPr-c H H 0 H H CF₃ N-Me Cl CH₂Cl CH₂Pr-c H H 0 H H CF₃ N-Me Cl CH₂Cl MeH H 0 H H CF₃ N-Me Cl CH₂Cl Me H H 0 H H CF₃ N-Me Cl CH₂Cl Me H H 0 H HCF₃ N-Me Cl CH₂Cl Me H H 0 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₃— H 0 H H CF₃N-Me Cl CH₂Cl —(CH₂)₄— H 0 H H CF₃ N-Me Cl CH₂Cl —(CH₂)₅— H 0 H H CF₃N-Me Cl CH₂Cl —(CH₂)₆— H 0 H H CF₃ N-Me Cl CH₂Cl Et H H 2 H H H N—H HCH₂Cl Me H H 2 H H Cl N-Et CF₃ CH₂Cl Me H H 2 H H Cl N-Pr CF₃ CH₂Cl Me HH 2 H H Cl N-Pr-i CF₃ CH₂Cl Me H H 2 H H Cl N-Bu-n CF₃ CH₂Cl Me H H 2 HH CF₃ N-Bu-n Cl CH₂Cl Me H H 2 H H Cl N-Bu-s CF₃ CH₂Cl Me H H 2 H H CF₃N-Bu-s Cl CH₂Cl Me H H 2 H H Cl N-Bu-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Bu-iCl CH₂Cl Me H H 2 H H CF₃ N-Bu-t H CH₂Cl Me H H 2 H H Cl N—CH₂Ph CF₃CH₂Cl Me H H 2 H H Cl N—CH₂CH₂OMe CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂CH₂OMeCl CH₂Cl Me H H 2 H H Cl N—CH₂SMe CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂SMe ClCH₂Cl Me H H 2 H H Cl N—CH₂OEt CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂OEt ClCH₂Cl Me H H 2 H H Cl N—CH₂CHF₂ CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂CHF₂ Cl

[0074] TABLE 14 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H ClN—CHF₂ CF₃ CH₂Cl Me H H 2 H H CF₃ N—CHF₂ Cl CH₂Cl Me H H 2 H H ClN—CH₂CF₃ CF₃ CH₂Cl Me H H 2 H H Cl N—CH₂OMe CF₃ CH₂Cl Me H H 2 H H ClN—CH₂COOEt CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂COOEt Cl CH₂Cl Me H H 2 H HCl N—CH₂CH═CH₂ CF₃ CH₂Cl Me H H 2 H H Cl N—CH₂C≡CH CF₃ CH₂Cl Me H H 2 HH Cl N—CH₂Pr-c CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂Pr-c Cl CH₂Cl Me H H 2 HH Cl N—CH₂Bu-c CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂Bu-c Cl CH₂Cl Me H H 2 HH Cl N—CH₂Pen-c CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂Pen-c Cl CH₂Cl Me H H 2H H Cl N—CH₂Hex-c CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂Hex-c Cl CH₂Cl Me H H2 H H Cl N—CH₂CCl═CHCl CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂CCl═CHCl Cl CH₂ClMe H H 2 H H CF₃ N-Hex-c Cl CH₂Cl Me H H 2 H H CF₃ N-Pen-c Cl CH₂Cl Me HH 2 H H Cl N—CH₂NMe₂ CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂NMe₂ Cl CH₂Cl Me HH 2 H H Cl N—CH₂NHMe CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂NHMe Cl CH₂Cl Me HH 2 H H Cl N—CH₂N(Me)COMe CF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂N(Me)COMe ClCH₂Cl Me H H 2 H H Cl N—CH₂N(Me)COCF₃ CF₃ CH₂Cl Me H H 2 H H CF₃N—CH₂N(Me)COCF₃ Cl CH₂Cl Me H H 2 H H Cl N—CH₂N(Me)SO₂Me CF₃ CH₂Cl Me HH 2 H H CF₃ N—CH₂N(Me)SO₂Me Cl CH₂Cl Me H H 2 H H Cl N—CH₂CONH₂ CF₃CH₂Cl Me H H 2 H H CF₃ N—CH₂CONH₂ Cl CH₂Cl Me H H 2 H H Cl N—CH₂CONHMeCF₃ CH₂Cl Me H H 2 H H CF₃ N—CH₂CONHMe Cl CH₂Cl Me H H 2 H H ClN—CH₂CONMe₂ CF₃

[0075] TABLE 15 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N—CH₂CONMe₂ Cl CH₂Cl Me H H 2 H H Cl N—CH₂COMe CF₃ CH₂Cl Me H H 2 H HCF₃ N—CH₂COMe Cl CH₂Cl Me H H 2 H H Cl N—CH₂CH₂COMe CF₃ CH₂Cl Me H H 2 HH CF₃ N—CH₂CH₂COMe Cl CH₂Cl Me H H 2 H H Cl N—CH₂COCF₃ CF₃ CH₂Cl Me H H2 H H CF₃ N—CH₂COCF₃ Cl CH₂Cl Me H H 2 H H CF₃ N-Me F CH₂Cl Me H H 2 H HCF₃ N-Me Me CH₂Cl Me H H 2 H H CF₃ N-Me CF₃ CH₂Cl Me H H 2 H H CF₃ N-MeOH CH₂Cl Me H H 2 H H CF₃ N-Me OBu-n CH₂Cl Me H H 2 H H CF₃ N-Me OBu-tCH₂Cl Me H H 2 H H CF₃ N-Me OCH₂CHF₂ CH₂Cl Me H H 2 H H CF₃ N-Me OCHF₂CH₂Cl Me H H 2 H H CF₃ N-Me OPen-c CH₂Cl Me H H 2 H H CF₃ N-Me OHex-cCH₂Cl Me H H 2 H H CF₃ N-Me OCH₂Pr-c CH₂Cl Me H H 2 H H CF₃ N-Me NH₂CH₂Cl Me H H 2 H H CF₃ N-Me NHMe CH₂Cl Me H H 2 H H CF₃ N-Me NMe₂ CH₂ClMe H H 2 H H CF₃ N-Me NHPh CH₂Cl Me H H 2 H H CF₃ N-Me NMePh CH₂Cl Me HH 2 H H CF₃ N-Me O-Ph(2-Cl) CH₂Cl Me H H 2 H H CF₃ N-Me O-Ph(3-Cl) CH₂ClMe H H 2 H H CF₃ N-Me O-Ph(4-C1) CH₂Cl Me H H 2 H H CF₃ N-Me O-Ph(4-F)CH₂Cl Me H H 2 H H CF₃ N-Me O-Ph(4-Me) CH₂Cl Me H H 2 H H CF₃ N-MeO-Ph(4-OMe) CH₂Cl Me H H 2 H H CF₃ N-Me SO₂Et CH₂Cl Me H H 2 H H CF₃N-Ph H CH₂Cl Me H H 2 H H CF₃ N-Ph F CH₂Cl Me H H 2 H H CF₃ N-Ph CNCH₂Cl Me H H 2 H H CF₃ N-Ph CF₃ CH₂Cl Me H H 2 H H CF₃ N-Ph Pr-n

[0076] TABLE 16 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N-Ph OBu-t CH₂Cl Me H H 2 H H CF₃ N-Ph OCH₂CHF₂ CH₂Cl Me H H 2 H H CF₃N-Ph OCHF₂ CH₂Cl Me H H 2 H H CF₃ N-Ph NH₂ CH₂Cl Me H H 2 H H CF₃ N-PhNHMe CH₂Cl Me H H 2 H H CF₃ N-Ph NMe₂ CH₂Cl Me H H 2 H H CF₃ N-Ph SO₂EtCH₂Cl Me H H 2 H H Cl N-Bu-t CF₃ CH₂Cl Me H H 2 H H CF₃ N-Ph(4-COMe) ClCH₂Cl Me H H 2 H H CF₃ N-Ph(4-CN) Cl CH₂Cl Me H H 2 H H CF₃N-Ph(4-COOMe) Cl CH₂Cl Me H H 2 H H CF₃ N-Ph(4-NO₂) Cl CH₂Cl Me H H 2 HH CF₃ N-Pyrimidin-2-yl Cl CH₂Cl Me H H 1 H H Cl N-Et CF₃ CH₂Cl Me H H 1H H Cl N-Pr CF₃ CH₂Cl Me H H 1 H H Cl N-Pr-i CF₃ CH₂Cl Me H H 1 H H ClN-Bu-n CF₃ CH₂Cl Me H H 1 H H CF₃ N-Bu-n Cl CH₂Cl Me H H 1 H H Cl N-Bu-sCF₃ CH₂Cl Me H H 1 H H CF₃ N-Bu-s Cl CH₂Cl Me H H 1 H H Cl N-Bu-i CF₃CH₂Cl Me H H 1 H H CF₃ N-Bu-i Cl CH₂Cl Me H H 1 H H CF₃ N-Bu-t H CH₂ClMe H H 1 H H Cl N—CH₂Ph CF₃ CH₂Cl Me H H 1 H H Cl N—CH₂CH₂OMe CF₃ CH₂ClMe H H 1 H H CF₃ N—CH₂CH₂OMe Cl CH₂Cl Me H H 1 H H Cl N—CH₂SMe CF₃ CH₂ClMe H H 1 H H CF₃ N—CH₂SMe Cl CH₂Cl Me H H 1 H H Cl N—CH₂OEt CF₃ CH₂Cl MeH H 1 H H CF₃ N—CH₂OEt Cl CH₂Cl Me H H 1 H H Cl N—CH₂CHF₂ CF₃ CH₂Cl Me HH 1 H H CF₃ N—CH₂CHF₂ Cl CH₂Cl Me H H 1 H H Cl N—CHF₂ CF₃ CH₂Cl Me H H 1H H CF₃ N—CHF₂ Cl CH₂Cl Me H H 1 H H Cl N—CH₂CF₃ CF₃

[0077] TABLE 17 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H ClN—CH₂OMe CF₃ CH₂Cl Me H H 1 H H Cl N—CH₂COOEt CF₃ CH₂Cl Me H H 1 H H CF₃N—CH₂COOEt Cl CH₂Cl Me H H 1 H H Cl N—CH₂CH═CH₂ CF₃ CH₂Cl Me H H 1 H HCl N—CH₂C≡CH CF₃ CH₂Cl Me H H 1 H H Cl N—CH₂Pr-c CF₃ CH₂Cl Me H H 1 H HCF₃ N—CH₂Pr-c Cl CH₂Cl Me H H 1 H H Cl N—CH₂Bu-c CF₃ CH₂Cl Me H H 1 H HCF₃ N—CH₂Bu-c Cl CH₂Cl Me H H 1 H H Cl N—CH₂Pen-c CF₃ CH₂Cl Me H H 1 H HCF₃ N—CH₂Pen-c Cl CH₂Cl Me H H 1 H H Cl N—CH₂Hex-c CF₃ CH₂Cl Me H H 1 HH CF₃ N—CH₂Hex-c Cl CH₂Cl Me H H 1 H H Cl N—CH₂CCl═CHCl CF₃ CH₂Cl Me H H1 H H CF₃ N—CH₂CCl═CHCl Cl CH₂Cl Me H H 1 H H CF₃ N-Hex-c Cl CH₂Cl Me HH 1 H H CF₃ N-Pen-c Cl CH₂Cl Me H H 1 H H Cl N—CH₂NMe₂ CF₃ CH₂Cl Me H H1 H H CF₃ N—CH₂NMe₂ Cl CH₂Cl Me H H 1 H H Cl N—CH₂NHMe CF₃ CH₂Cl Me H H1 H H CF₃ N—CH₂NHMe Cl CH₂Cl Me H H 1 H H Cl N—CH₂N(Me)COMe CF₃ CH₂Cl MeH H 1 H H CF₃ N—CH₂N(Me)COMe Cl CH₂Cl Me H H 1 H H Cl N—CH₂N(Me)COCF₃CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂N(Me)COCF₃ Cl CH₂Cl Me H H 1 H H ClN—CH₂N(Me)SO₂Me CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂N(Me)SO₂Me Cl CH₂Cl Me HH 1 H H Cl N—CH₂CONH₂ CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂CONH₂ Cl CH₂Cl MeH H 1 H H Cl N—CH₂CONHMe CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂CONHMe Cl CH₂ClMe H H 1 H H Cl N—CH₂CONMe₂ CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂CONMe₂ ClCH₂Cl Me H H 1 H H Cl N—CH₂COMe CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂COMe Cl

[0078] TABLE 18 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H ClN—CH₂CH₂COMe CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂CH₂COMe Cl CH₂Cl Me H H 1 HH Cl N—CH₂COCF₃ CF₃ CH₂Cl Me H H 1 H H CF₃ N—CH₂COCF₃ Cl CH₂Cl Me H H 1H H CF₃ N-Me F CH₂Cl Me H H 1 H H CF₃ N-Me Me CH₂Cl Me H H 1 H H CF₃N-Me CF₃ CH₂Cl Me H H 1 H H CF₃ N-Me OH CH₂Cl Me H H 1 H H CF₃ N-MeOBu-n CH₂Cl Me H H 1 H H CF₃ N-Me OBu-t CH₂Cl Me H H 1 H H CF₃ N-MeOCH₂CHF₂ CH₂Cl Me H H 1 H H CF₃ N-Me OCHF₂ CH₂Cl Me H H 1 H H CF₃ N-MeOPen-c CH₂Cl Me H H 1 H H CF₃ N-Me OHex-c CH₂Cl Me H H 1 H H CF₃ N-MeOCH₂Pr-c CH₂Cl Me H H 1 H H CF₃ N-Me NH₂ CH₂Cl Me H H 1 H H CF₃ N-MeNHMe CH₂Cl Me H H 1 H H CF₃ N-Me NMe₂ CH₂Cl Me H H 1 H H CF₃ N-Me NHPhCH₂Cl Me H H 1 H H CF₃ N-Me NMePh CH₂Cl Me H H 1 H H CF₃ N-Me O-Ph(2-Cl)CH₂Cl Me H H 1 H H CF₃ N-Me O-Ph(3-Cl) CH₂Cl Me H H 1 H H CF₃ N-MeO-Ph(4-C1) CH₂Cl Me H H 1 H H CF₃ N-Me O-Ph(4-F) CH₂Cl Me H H 1 H H CF₃N-Me O-Ph(4-Me) CH₂Cl Me H H 1 H H CF₃ N-Me O-Ph(4-OMe) CH₂Cl Me H H 1 HH CF₃ N-Me SO₂Et CH₂Cl Me H H 1 H H CF₃ N-Ph H CH₂Cl Me H H 1 H H CF₃N-Ph F CH₂Cl Me H H 1 H H CF₃ N-Ph CN CH₂Cl Me H H 1 H H CF₃ N-Ph CF₃CH₂Cl Me H H 1 H H CF₃ N-Ph Pr-n CH₂Cl Me H H 1 H H CF₃ N-Ph OBu-t CH₂ClMe H H 1 H H CF₃ N-Ph OCH₂CHF₂ CH₂Cl Me H H 1 H H CF₃ N-Ph OCHF₂

[0079] TABLE 19 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H CF₃N-Ph NH₂ CH₂Cl Me H H 1 H H CF₃ N-Ph NHMe CH₂Cl Me H H 1 H H CF₃ N-PhNMe₂ CH₂Cl Me H H 1 H H CF₃ N-Ph SO₂Et CH₂Cl Me H H 1 H H Cl N-Bu-t CF₃CH₂Cl Me H H 1 H H CF₃ N-Ph(4-COMe) Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(4-CN)Cl CH₂Cl Me H H 1 H H CF₃ N-Ph(4-COOMe) Cl CH₂Cl Me H H 1 H H CF₃N-Ph(4-NO₂) Cl CH₂Cl Me H H 1 H H CF₃ N-Pyrimidin-2-yl Cl CH₂Cl Me H H 0H H Cl N-Et CF₃ CH₂Cl Me H H 0 H H Cl N-Pr CF₃ CH₂Cl Me H H 0 H H ClN-Pr-i CF₃ CH₂Cl Me H H 0 H H Cl N-Bu-n CF₃ CH₂Cl Me H H 0 H H CF₃N-Bu-n Cl CH₂Cl Me H H 0 H H Cl N-Bu-s CF₃ CH₂Cl Me H H 0 H H CF₃ N-Bu-sCl CH₂Cl Me H H 0 H H Cl N-Bu-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Bu-i ClCH₂Cl Me H H 0 H H CF₃ N-Bu-t H CH₂Cl Me H H 0 H H Cl N—CH₂Ph CF₃ CH₂ClMe H H 0 H H Cl N—CH₂CH₂OMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CH₂OMe ClCH₂Cl Me H H 0 H H Cl N—CH₂SMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂SMe ClCH₂Cl Me H H 0 H H Cl N—CH₂OEt CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂OEt ClCH₂Cl Me H H 0 H H Cl N—CH₂CHF₂ CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CHF₂ ClCH₂Cl Me H H 0 H H Cl N—CHF₂ CF₃ CH₂Cl Me H H 0 H H CF₃ N—CHF₂ Cl CH₂ClMe H H 0 H H Cl N—CH₂CF₃ CF₃ CH₂Cl Me H H 0 H H Cl N—CH₂OMe CF₃ CH₂Cl MeH H 0 H H Cl N—CH₂COOEt CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂COOEt Cl

[0080] TABLE 20 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H ClN—CH₂CH═CH₂ CF₃ CH₂Cl Me H H 0 H H Cl N—CH₂C≡CH CF₃ CH₂Cl Me H H 0 H HCl N—CH₂Pr-c CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂Pr-c Cl CH₂Cl Me H H 0 H HCl N—CH₂Bu-c CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂Bu-c Cl CH₂Cl Me H H 0 H HCl N—CH₂Pen-c CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂Pen-c Cl CH₂Cl Me H H 0 HH Cl N—CH₂Hex-c CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂Hex-c Cl CH₂Cl Me H H 0H H Cl N—CH₂CCl═CHCl CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CCl═CHCl Cl CH₂ClMe H H 0 H H CF₃ N-Hex-c Cl CH₂Cl Me H H 0 H H CF₃ N-Pen-c Cl CH₂Cl Me HH 0 H H Cl N—CH₂NMe₂ CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂NMe₂ Cl CH₂Cl Me HH 0 H H Cl N—CH₂NHMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂NHMe Cl CH₂Cl Me HH 0 H H Cl N—CH₂N(Me)COMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂N(Me)COMe ClCH₂Cl Me H H 0 H H Cl N—CH₂N(Me)COCF₃ CF₃ CH₂Cl Me H H 0 H H CF₃N—CH₂N(Me)COCF₃ Cl CH₂Cl Me H H 0 H H Cl N—CH₂N(Me)SO₂Me CF₃ CH₂Cl Me HH 0 H H CF₃ N—CH₂N(Me)SO₂Me Cl CH₂Cl Me H H 0 H H Cl N—CH₂CONH₂ CF₃CH₂Cl Me H H 0 H H CF₃ N—CH₂CONH₂ Cl CH₂Cl Me H H 0 H H Cl N—CH₂CONHMeCF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CONHMe Cl CH₂Cl Me H H 0 H H ClN—CH₂CONMe₂ CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CONMe₂ Cl CH₂Cl Me H H 0 H HCl N—CH₂COMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂COMe Cl CH₂Cl Me H H 0 H HCl N—CH₂CH₂COMe CF₃ CH₂Cl Me H H 0 H H CF₃ N—CH₂CH₂COMe Cl CH₂Cl Me H H0 H H Cl N—CH₂COCF₃ CF₃

[0081] TABLE 21 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N—CH₂COCF₃ Cl CH₂Cl Me H H 0 H H CF₃ N-Me F CH₂Cl Me H H 0 H H CF₃ N-MeMe CH₂Cl Me H H 0 H H CF₃ N-Me CF₃ CH₂Cl Me H H 0 H H CF₃ N-Me OH CH₂ClMe H H 0 H H CF₃ N-Me OBu-n CH₂Cl Me H H 0 H H CF₃ N-Me OBu-t CH₂Cl Me HH 0 H H CF₃ N-Me OCH₂CHF₂ CH₂Cl Me H H 0 H H CF₃ N-Me OCHF₂ CH₂Cl Me H H0 H H CF₃ N-Me OPen-c CH₂Cl Me H H 0 H H CF₃ N-Me OHex-c CH₂Cl Me H H 0H H CF₃ N-Me OCH₂Pr-c CH₂Cl Me H H 0 H H CF₃ N-Me NH₂ CH₂Cl Me H H 0 H HCF₃ N-Me NHMe CH₂Cl Me H H 0 H H CF₃ N-Me NMe₂ CH₂Cl Me H H 0 H H CF₃N-Me NHPh CH₂Cl Me H H 0 H H CF₃ N-Me NMePh CH₂Cl Me H H 0 H H CF₃ N-MeO-Ph(2-Cl) CH₂Cl Me H H 0 H H CF₃ N-Me O-Ph(3-Cl) CH₂Cl Me H H 0 H H CF₃N-Me O-Ph(4-C1) CH₂Cl Me H H 0 H H CF₃ N-Me O-Ph(4-F) CH₂Cl Me H H 0 H HCF₃ N-Me O-Ph(4-Me) CH₂Cl Me H H 0 H H CF₃ N-Me O-Ph(4-OMe) CH₂Cl Me H H0 H H CF₃ N-Me SO₂Et CH₂Cl Me H H 0 H H CF₃ N-Ph H CH₂Cl Me H H 0 H HCF₃ N-Ph F CH₂Cl Me H H 0 H H CF₃ N-Ph CN CH₂Cl Me H H 0 H H CF₃ N-PhCF₃ CH₂Cl Me H H 0 H H CF₃ N-Ph Pr-n CH₂Cl Me H H 0 H H CF₃ N-Ph OBu-4CH₂Cl Me H H 0 H H CF₃ N-Ph OCH₂CHF₂ CH₂Cl Me H H 0 H H CF₃ N-Ph OCHF₂CH₂Cl Me H H 0 H H CF₃ N-Ph NH₂ CH₂Cl Me H H 0 H H CF₃ N-Ph NHMe CH₂ClMe H H 0 H H CF₃ N-Ph NMe₂

[0082] TABLE 22 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N-Ph SO₂Et CH₂Cl Me H H 0 H H Cl N-Bu-t CF₃ CH₂Cl Me H H 0 H H CF₃N-Ph(4-COMe) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(4-CN) Cl CH₂Cl Me H H 0 H HCF₃ N-Ph(4-COOMe) Cl CH₂Cl Me H H 0 H H CF₃ N-Ph(4-NO₂) Cl CH₂Cl Me H H0 H H CF₃ N-Pyrimidin-2-yl Cl CH₂Cl Me H H 2 H H CF₃ N—NH₂ Cl CH₂Cl Me HH 2 H H Cl N—NH₂ CF₃ CH₂Cl Me H H 2 H H OH N-Me CF₃ CH₂Cl Me H H 2 H HOMe N-Me CF₃ CH₂Cl Me H H 2 H H OEt N-Me CF₃ CH₂Cl Me H H 2 H H OPr-iN-Me CF₃ CH₂Cl Me H H 2 H H OCHF₂ N-Me CF₃ CH₂Cl Me H H 2 H H OCH₂CHF₂N-Me CF₃ CH₂Cl Me H H 2 H H OCH₂CF₃ N-Me CF₃ CH₂Cl Me H H 2 H H OCHF₂N-Me OCHF₂ CH₂Cl Me H H 2 H H CF₃ N-Me CONH₂ CH₂Cl Me H H 2 H H CF₃ N-MeCONHMe CH₂Cl Me H H 2 H H CF₃ N-Me CONMe₂ CH₂Cl Me H H 2 H H CF₃ N-MeCOOMe CH₂Cl Me H H 2 H H CF₃ N-Me COOEt CH₂Cl Me H H 2 H H CF₃ N-MeCOOPr-i CH₂Cl Me H H 2 H H CF₃ N-Me COMe CH₂Cl Me H H 2 H H CF₃ N-MeCOEt CH₂Cl Me H H 2 H H OCHF₂ N-Ph CF₃ CH₂Cl Me H H 2 H H OCH₂CHF₂ N-PhCF₃ CH₂Cl Me H H 2 H H OCH₂CF₃ N-Ph CF₃ CH₂Cl Me H H 2 H H CF₃ N—CHF₂ FCH₂Cl Me H H 2 H H CF₃ N—CHF₂ OMe CH₂Cl Me H H 2 H H CF₃ N—CHF₂ OCHF₂CH₂Cl Me H H 2 H H Cl N—CHF₂ Cl CH₂Cl Me H H 2 H H F N—CHF₂ CF₃ CH₂Cl MeH H 2 H H OMe N—CHF₂ CF₃ CH₂Cl Me H H 2 H H OCHF₂ N—CHF₂ CF₃

[0083] TABLE 23 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H OCHF₂N—CHF₂ OCHF₂ CH₂Cl Me H H 2 H H Cl N-Et Cl CH₂Cl Me H H 2 H H Cl N-Pr-iCl CH₂Cl Me H H 2 H H Cl N-Pr Cl CH₂Cl Me H H 2 H H Cl N—CH₂Pr-c ClCH₂Cl Me H H 2 H H Cl N—CH₂C≡CH Cl CH₂Cl Me H H 2 H H Cl N—CH₂OMe ClCH₂Cl Me H H 2 H H OCHF₂ N-Et OCHF₂ CH₂Cl Me H H 2 H H OCHF₂ N-Pr-iOCHF₂ CH₂Cl Me H H 2 H H OCHF₂ N-Pr OCHF₂ CH₂Cl Me H H 2 H H OCHF₂N—CH₂Pr-c OCHF₂ CH₂Cl Me H H 2 H H OCHF₂ N—CH₂C≡CH OCHF₂ CH₂Cl Me H H 2H H OCHF₂ N—CH₂OMe OCHF₂ CH₂Cl Me H H 2 H H CF₃ N—CH₂Pr-c F CH₂Cl Me H H2 H H CF₃ N—CH₂Pr-c OMe CH₂Cl Me H H 2 H H CF₃ N—CH₂Pr-c OCHF₂ CH₂Cl MeH H 2 H H F N—CH₂Pr-c CF₃ CH₂Cl Me H H 2 H H OMe N—CH₂Pr-c CF₃ CH₂Cl MeH H 2 H H OCHF₂ N—CH₂Pr-c CF₃ CH₂Cl Me H H 1 H H CF₃ N—NH₂ Cl CH₂Cl Me HH 1 H H Cl N—NH₂ CF₃ CH₂Cl Me H H 1 H H OH N-Me CF₃ CH₂Cl Me H H 1 H HOMe N-Me CF₃ CH₂Cl Me H H 1 H H OEt N-Me CF₃ CH₂Cl Me H H 1 H H OPr-iN-Me CF₃ CH₂Cl Me H H 1 H H OCHF₂ N-Me CF₃ CH₂Cl Me H H 1 H H OCH₂CHF₂N-Me CF₃ CH₂Cl Me H H 1 H H OCH₂CF₃ N-Me CF₃ CH₂Cl Me H H 1 H H OCHF₂N-Me OCHF₂ CH₂Cl Me H H 1 H H CF₃ N-Me CONH₂ CH₂Cl Me H H 1 H H CF₃ N-MeCONHMe CH₂Cl Me H H 1 H H CF₃ N-Me CONMe₂ CH₂Cl Me H H 1 H H CF₃ N-MeCOOMe CH₂Cl Me H H 1 H H CF₃ N-Me COOEt CH₂Cl Me H H 1 H H CF₃ N-MeCOOPr-i

[0084] TABLE 24 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 1 H H CF₃N-Me COMe CH₂Cl Me H H 1 H H CF₃ N-Me COEt CH₂Cl Me H H 1 H H OCHF₂ N-PhCF₃ CH₂Cl Me H H 1 H H OCH₂CHF₂ N-Ph CF₃ CH₂Cl Me H H 1 H H OCH₂CF₃ N-PhCF₃ CH₂Cl Me H H 1 H H CF₃ N—CHF₂ F CH₂Cl Me H H 1 H H CF₃ N—CHF₂ OMeCH₂Cl Me H H 1 H H CF₃ N—CHF₂ OCHF₂ CH₂Cl Me H H 1 H H Cl N—CHF₂ ClCH₂Cl Me H H 1 H H F N—CHF₂ CF₃ CH₂Cl Me H H 1 H H OMe N—CHF₂ CF₃ CH₂ClMe H H 1 H H OCHF₂ N—CHF₂ CF₃ CH₂Cl Me H H 1 H H OCHF₂ N—CHF₂ OCHF₂CH₂Cl Me H H 1 H H Cl N-Et Cl CH₂Cl Me H H 1 H H Cl N-Pr-i Cl CH₂Cl Me HH 1 H H Cl N-Pr Cl CH₂Cl Me H H 1 H H Cl N—CH₂Pr-c Cl CH₂Cl Me H H 1 H HCl N—CH₂C≡CH Cl CH₂Cl Me H H 1 H H Cl N—CH₂OMe Cl CH₂Cl Me H H 1 H HOCHF₂ N-Et OCHF₂ CH₂Cl Me H H 1 H H OCHF₂ N-Pr-i OCHF₂ CH₂Cl Me H H 1 HH OCHF₂ N-Pr OCHF₂ CH₂Cl Me H H 1 H H OCHF₂ N—CH₂Pr-c OCHF₂ CH₂Cl Me H H1 H H OCHF₂ N—CH₂C≡CH OCHF₂ CH₂Cl Me H H 1 H H OCHF₂ N—CH₂OMe OCHF₂CH₂Cl Me H H 1 H H CF₃ N—CH₂Pr-c F CH₂Cl Me H H 1 H H CF₃ N—CH₂Pr-c OMeCH₂Cl Me H H 1 H H CF₃ N—CH₂Pr-c OCHF₂ CH₂Cl Me H H 1 H H F N—CH₂Pr-cCF₃ CH₂Cl Me H H 1 H H OMe N—CH₂Pr-c CF₃ CH₂Cl Me H H 1 H H OCHF₂N—CH₂Pr-c CF₃ CH₂Cl Me H H 0 H H CF₃ N—NH₂ Cl CH₂Cl Me H H 0 H H ClN—NH₂ CF₃ CH₂Cl Me H H 0 H H OH N-Me CF₃ CH₂Cl Me H H 0 H H OMe N-Me CF₃

[0085] TABLE 25 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H OEtN-Me CF₃ CH₂Cl Me H H 0 H H OPr-i N-Me CF₃ CH₂Cl Me H H 0 H H OCHF₂ N-MeCF₃ CH₂Cl Me H H 0 H H OCH₂CHF₂ N-Me CF₃ CH₂Cl Me H H 0 H H OCH₂CF₃ N-MeCF₃ CH₂Cl Me H H 0 H H OCHF₂ N-Me OCHF₂ CH₂Cl Me H H 0 H H CF₃ N-MeCONH₂ CH₂Cl Me H H 0 H H CF₃ N-Me CONHMe CH₂Cl Me H H 0 H H CF₃ N-MeCONMe₂ CH₂Cl Me H H 0 H H CF₃ N-Me COOMe CH₂Cl Me H H 0 H H CF₃ N-MeCOOEt CH₂Cl Me H H 0 H H CF₃ N-Me COOPr-i CH₂Cl Me H H 0 H H CF₃ N-MeCOMe CH₂Cl Me H H 0 H H CF₃ N-Me COEt CH₂Cl Me H H 0 H H OCHF₂ N-Ph CF₃CH₂Cl Me H H 0 H H OCH₂CHF₂ N-Ph CF₃ CH₂Cl Me H H 0 H H OCH₂CF₃ N-Ph CF₃CH₂Cl Me H H 0 H H CF₃ N—CHF₂ F CH₂Cl Me H H 0 H H CF₃ N—CHF₂ OMe CH₂ClMe H H 0 H H CF₃ N—CHF₂ OCHF₂ CH₂Cl Me H H 0 H H Cl N—CHF₂ Cl CH₂Cl Me HH 0 H H F N—CHF₂ CF₃ CH₂Cl Me H H 0 H H OMe N—CHF₂ CF₃ CH₂Cl Me H H 0 HH OCHF₂ N—CHF₂ CF₃ CH₂Cl Me H H 0 H H OCHF₂ N—CHF₂ OCHF₂ CH₂Cl Me H H 0H H Cl N-Et Cl CH₂Cl Me H H 0 H H Cl N-Pr-i Cl CH₂Cl Me H H 0 H H ClN-Pr Cl CH₂Cl Me H H 0 H H Cl N—CH₂Pr-c Cl CH₂Cl Me H H 0 H H ClN—CH₂C≡CH Cl CH₂Cl Me H H 0 H H Cl N—CH₂OMe Cl CH₂Cl Me H H 0 H H OCHF₂N-Et OCHF₂ CH₂Cl Me H H 0 H H OCHF₂ N-Pr-i OCHF₂ CH₂Cl Me H H 0 H HOCHF₂ N-Pr OCHF₂ CH₂Cl Me H H 0 H H OCHF₂ N—CH₂Pr-c OCHF₂

[0086] TABLE 26 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H OCHF₂N—CH₂C≡CH OCHF₂ CH₂Cl Me H H 0 H H OCHF₂ N—CH₂OMe OCHF₂ CH₂Cl Me H H 0 HH CF₃ N—CH₂Pr-c F CH₂Cl Me H H 0 H H CF₃ N—CH₂Pr-c OMe CH₂Cl Me H H 0 HH CF₃ N—CH₂Pr-c OCHF₂ CH₂Cl Me H H 0 H H F N—CH₂Pr-c CF₃ CH₂Cl Me H H 0H H OMe N—CH₂Pr-c CF₃ CH₂Cl Me H H 0 H H OCHF₂ N—CH₂Pr-c CF₃ CH₂Cl Me HH 2 H H CF₃ N—(CH₂)₂O— CH₂Cl Me H H 2 H H CF₃ N—(CH₂)₃O— CH₂Cl Me H H 2H H CF₃ N—(CH₂)₂S— CH₂Cl Me H H 2 H H CF₃ N—(CH₂)₂SO₂— CH₂Cl Me H H 2 HH Cl N—(CH₂)₂O— CH₂Cl Me H H 2 H H Cl N—(CH₂)₃O— CH₂Cl Me H H 2 H H ClN—(CH₂)₂S— CH₂Cl Me H H 2 H H Cl N—(CH₂)₂SO₂— CH₂Cl Me H H 1 H H CF₃N—(CH₂)₂O— CH₂Cl Me H H 1 H H CF₃ N—(CH₂)₃O— CH₂Cl Me H H 1 H H CF₃N—(CH₂)₂S— CH₂Cl Me H H 1 H H CF₃ N—(CH₂)₂SO₂— CH₂Cl Me H H 1 H H ClN—(CH₂)₂O— CH₂Cl Me H H 1 H H Cl N—(CH₂)₃O— CH₂Cl Me H H 1 H H ClN—(CH₂)₂S— CH₂Cl Me H H 1 H H Cl N—(CH₂)₂SO₂— CH₂Cl Me H H 0 H H CF₃N—(CH₂)₂O— CH₂Cl Me H H 0 H H CF₃ N—(CH₂)₃O— CH₂Cl Me H H 0 H H CF₃N—(CH₂)₂S— CH₂Cl Me H H 0 H H CF₃ N—(CH₂)₂SO₂— CH₂Cl Me H H 0 H H ClN—(CH₂)₂O— CH₂Cl Me H H 0 H H Cl N—(CH₂)₃O— CH₂Cl Me H H 0 H H ClN—(CH₂)₂S— CH₂Cl Me H H 0 H H Cl N—(CH₂)₂SO₂— CH₂Cl Me H H 2 H H CF₃N-Et F CH₂Cl Me H H 2 H H F N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et Br

[0087] TABLE 27 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H BrN-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et CNCH₂Cl Me H H 2 H H CN N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et Me CH₂Cl Me HH 2 H H Me N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et Et CH₂Cl Me H H 2 H H EtN-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et OH CH₂Cl Me H H 2 H H CF₃ N-Et OMeCH₂Cl Me H H 2 H H OMe N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et OEt CH₂Cl MeH H 2 H H OEt N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et OPr-i CH₂Cl Me H H 2H H OPr-i N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et OPr CH₂Cl Me H H 2 H HCF₃ N-Et OBu-t CH₂Cl Me H H 2 H H CF₃ N-Et OPh CH₂Cl Me H H 2 H H CF₃N-Et OCH₂Ph CH₂Cl Me H H 2 H H CF₃ N-Et OCH₂CH═CH₂ CH₂Cl Me H H 2 H HCF₃ N-Et OCH(Me)CH═CH₂ CH₂Cl Me H H 2 H H CF₃ N-Et OCH₂C≡CH CH₂Cl Me H H2 H H CF₃ N-Et OCH(Me)C≡CH CH₂Cl Me H H 2 H H CF₃ N-Et OCHF₂ CH₂Cl Me HH 2 H H OCHF₂ N-Et CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et OCH₂CF₃ CH₂Cl Me H H2 H H CF₃ N-Et OCH₂CHF₂ CH₂Cl Me H H 2 H H OCH₂CHF₂ N-Et CF₃ CH₂Cl Me HH 2 H H CF₃ N-Et SMe CH₂Cl Me H H 2 H H CF₃ N-Et SOMe CH₂Cl Me H H 2 H HCF₃ N-Et SO₂Me CH₂Cl Me H H 2 H H CF₃ N-Et SEt CH₂Cl Me H H 2 H H CF₃N-Et SOEt CH₂Cl Me H H 2 H H CF₃ N-Et SO₂Et CH₂Cl Me H H 2 H H CF₃ N-EtSPr-i

[0088] TABLE 28 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N-Et SOPr-i CH₂Cl Me H H 2 H H CF₃ N-Et SO₂Pr-i CH₂Cl Me H H 2 H H CF₃N-Et SCF₃ CH₂Cl Me H H 2 H H CF₃ N-Et SOCF₃ CH₂Cl Me H H 2 H H CF₃ N-EtSO₂CF₃ CH₂Cl Me H H 2 H H CF₃ N-Et SCHF₂ CH₂Cl Me H H 2 H H CF₃ N-EtSOCHF₂ CH₂Cl Me H H 2 H H CF₃ N-Et SO₂CHF₂ CH₂Cl Me H H 2 H H CHF₂ N-EtCl CH₂Cl Me H H 2 H H CHF₂ N-Et OMe CH₂Cl Me H H 2 H H CHF₂ N-Et OCHF₂CH₂Cl Me H H 2 H H CHF₂ N-Et CN CH₂Cl Me H H 2 H H CHF₂ N-Et Me CH₂Cl MeH H 2 H H Me N-Et Cl CH₂Cl Me H H 2 H H Me N-Et OMe CH₂Cl Me H H 2 H HMe N-Et OCHF₂ CH₂Cl Me H H 2 H H Me N-Et CN CH₂Cl Me H H 2 H H Me N-EtMe CH₂Cl Me H H 2 H H Et N-Et Cl CH₂Cl Me H H 2 H H Et N-Et OMe CH₂Cl MeH H 2 H H Et N-Et OCHF₂ CH₂Cl Me H H 2 H H Et N-Et CN CH₂Cl Me H H 2 H HEt N-Et Me CH₂Cl Me H H 2 H H OCHF₂ N-Et Cl CH₂Cl Me H H 0 H H CF₃ N-EtF CH₂Cl Me H H 0 H H F N-Et CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et Br CH₂Cl MeH H 0 H H Br N-Et CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et CF₃ CH₂Cl Me H H 0 H HCF₃ N-Et CN CH₂Cl Me H H 0 H H CN N-Et CF₃ CH₂Cl Me H H 0 H H CF₃ N-EtMe CH₂Cl Me H H 0 H H Me N-Et CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et Et CH₂ClMe H H 0 H H Et N-Et CF₃

[0089] TABLE 29 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N-Et OH CH₂Cl Me H H 0 H H CF₃ N-Et OMe CH₂Cl Me H H 0 H H OMe N-Et CF₃CH₂Cl Me H H 0 H H CF₃ N-Et OEt CH₂Cl Me H H 0 H H OEt N-Et CF₃ CH₂Cl MeH H 0 H H CF₃ N-Et OPr-i CH₂Cl Me H H 0 H H OPr-i N-Et CF₃ CH₂Cl Me H H0 H H CF₃ N-Et OPr CH₂Cl Me H H 0 H H CF₃ N-Et OBu-t CH₂Cl Me H H 0 H HCF₃ N-Et OPh CH₂Cl Me H H 0 H H CF₃ N-Et OCH₂Ph CH₂Cl Me H H 0 H H CF₃N-Et OCH₂CH═CH₂ CH₂Cl Me H H 0 H H CF₃ N-Et OCH(Me)CH═CH₂ CH₂Cl Me H H 0H H CF₃ N-Et OCH₂C≡CH CH₂Cl Me H H 0 H H CF₃ N-Et OCH(Me)C≡CH CH₂Cl Me HH 0 H H CF₃ N-Et OCHF₂ CH₂Cl Me H H 0 H H OCHF₂ N-Et CF₃ CH₂Cl Me H H 0H H CF₃ N-Et OCH₂CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et OCH₂CHF₂ CH₂Cl Me H H 0H H OCH₂CHF₂ N-Et CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et SMe CH₂Cl Me H H 0 H HCF₃ N-Et SOMe CH₂Cl Me H H 0 H H CF₃ N-Et SO₂Me CH₂Cl Me H H 0 H H CF₃N-Et SEt CH₂Cl Me H H 0 H H CF₃ N-Et SOEt CH₂Cl Me H H 0 H H CF₃ N-EtSO₂Et CH₂Cl Me H H 0 H H CF₃ N-Et SPr-i CH₂Cl Me H H 0 H H CF₃ N-EtSOPr-i CH₂Cl Me H H 0 H H CF₃ N-Et SO₂Pr-i CH₂Cl Me H H 0 H H CF₃ N-EtSCF₃ CH₂Cl Me H H 0 H H CF₃ N-Et SOCF₃ CH₂Cl Me H H 0 H H CF₃ N-EtSO₂CF₃ CH₂Cl Me H H 0 H H CF₃ N-Et SCHF₂ CH₂Cl Me H H 0 H H CF₃ N-EtSOCHF₂ CH₂Cl Me H H 0 H H CF₃ N-Et SO₂CHF₂

[0090] TABLE 30 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CHF₂N-Et Cl CH₂Cl Me H H 0 H H CHF₂ N-Et OMe CH₂Cl Me H H 0 H H CHF₂ N-EtOCHF₂ CH₂Cl Me H H 0 H H CHF₂ N-Et CN CH₂Cl Me H H 0 H H CHF₂ N-Et MeCH₂Cl Me H H 0 H H Me N-Et Cl CH₂Cl Me H H 0 H H Me N-Et OMe CH₂Cl Me HH 0 H H Me N-Et OCHF₂ CH₂Cl Me H H 0 H H Me N-Et CN CH₂Cl Me H H 0 H HMe N-Et Me CH₂Cl Me H H 0 H H Et N-Et Cl CH₂Cl Me H H 0 H H Et N-Et OMeCH₂Cl Me H H 0 H H Et N-Et OCHF₂ CH₂Cl Me H H 0 H H Et N-Et CN CH₂Cl MeH H 0 H H Et N-Et Me CH₂Cl Me H H 0 H H OCHF₂ N-Et Cl CH₂Cl Me H H 2 H HCF₃ N-Me Et CH₂Cl Me H H 2 H H Me N-Me CF₃ CH₂Cl Me H H 2 H H CF₃ N-MeBr CH₂Cl Me H H 2 H H Br N-Me CF₃ CH₂Cl Me H H 0 H H CF₃ N-Me Et CH₂ClMe H H 0 H H Me N-Me CF₃ CH₂Cl Me H H 0 H H CF₃ N-Me Br CH₂Cl Me H H 0 HH Br N-Me CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i F CH₂Cl Me H H 2 H H FN-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i Br CH₂Cl Me H H 2 H H Br N-Pr-iCF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i CNCH₂Cl Me H H 2 H H CN N-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i Me CH₂ClMe H H 2 H H Me N-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i Et CH₂Cl Me H H2 H H Et N-Pr-i CF₃

[0091] TABLE 31 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CF₃N-Pr-i OH CH₂Cl Me H H 2 H H CF₃ N-Pr-i OMe CH₂Cl Me H H 2 H H OMeN-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i OEt CH₂Cl Me H H 2 H H OEtN-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i OPr-i CH₂Cl Me H H 2 H H OPr-iN-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i OPr CH₂Cl Me H H 2 H H CF₃N-Pr-i OBu-t CH₂Cl Me H H 2 H H CF₃ N-Pr-i OPh CH₂Cl Me H H 2 H H CF₃N-Pr-i OCH₂Ph CH₂Cl Me H H 2 H H CF₃ N-Pr-i OCH₂CH═CH₂ CH₂Cl Me H H 2 HH CF₃ N-Pr-i OCH(Me)CH═CH₂ CH₂Cl Me H H 2 H H CF₃ N-Pr-i OCH₂C≡CH CH₂ClMe H H 2 H H CF₃ N-Pr-i OCH(Me)C≡CH CH₂Cl Me H H 2 H H CF₃ N-Pr-i OCHF₂CH₂Cl Me H H 2 H H OCHF₂ N-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-iOCH₂CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i OCH₂CHF₂ CH₂Cl Me H H 2 H HOCH₂CHF₂ N-Pr-i CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i SMe CH₂Cl Me H H 2 H HCF₃ N-Pr-i SOMe CH₂Cl Me H H 2 H H CF₃ N-Pr-i SO₂Me CH₂Cl Me H H 2 H HCF₃ N-Pr-i SEt CH₂Cl Me H H 2 H H CF₃ N-Pr-i SOEt CH₂Cl Me H H 2 H H CF₃N-Pr-i SO₂Et CH₂Cl Me H H 2 H H CF₃ N-Pr-i SPr-i CH₂Cl Me H H 2 H H CF₃N-Pr-i SOPr-i CH₂Cl Me H H 2 H H CF₃ N-Pr-i SO₂Pr-i CH₂Cl Me H H 2 H HCF₃ N-Pr-i SCF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i SOCF₃ CH₂Cl Me H H 2 H HCF₃ N-Pr-i SO₂CF₃ CH₂Cl Me H H 2 H H CF₃ N-Pr-i SCHF₂ CH₂Cl Me H H 2 H HCF₃ N-Pr-i SOCHF₂ CH₂Cl Me H H 2 H H CF₃ N-Pr-i SO₂CHF₂

[0092] TABLE 32 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 2 H H CHF₂N-Pr-i Cl CH₂Cl Me H H 2 H H CHF₂ N-Pr-i OMe CH₂Cl Me H H 2 H H CHF₂N-Pr-i OCHF₂ CH₂Cl Me H H 2 H H CHF₂ N-Pr-i CN CH₂Cl Me H H 2 H H CHF₂N-Pr-i Me CH₂Cl Me H H 2 H H Me N-Pr-i Cl CH₂Cl Me H H 2 H H Me N-Pr-iOMe CH₂Cl Me H H 2 H H Me N-Pr-i OCHF₂ CH₂Cl Me H H 2 H H Me N-Pr-i CNCH₂Cl Me H H 2 H H Me N-Pr-i Me CH₂Cl Me H H 2 H H Et N-Pr-i Cl CH₂Cl MeH H 2 H H Et N-Pr-i OMe CH₂Cl Me H H 2 H H Et N-Pr-i OCHF₂ CH₂Cl Me H H2 H H Et N-Pr-i CN CH₂Cl Me H H 2 H H Et N-Pr-i Me CH₂Cl Me H H 2 H HOCHF₂ N-Pr-i Cl CH₂Cl Me H H 0 H H CF₃ N-Pr-i F CH₂Cl Me H H 0 H H FN-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i Br CH₂Cl Me H H 0 H H Br N-Pr-iCF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i CNCH₂Cl Me H H 0 H H CN N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i Me CH₂ClMe H H 0 H H Me N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i Et CH₂Cl Me H H0 H H Et N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i OH CH₂Cl Me H H 0 H HCF₃ N-Pr-i OMe CH₂Cl Me H H 0 H H OMe N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃N-Pr-i OEt CH₂Cl Me H H 0 H H OEt N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃N-Pr-i OPr-i CH₂Cl Me H H 0 H H OPr-i N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃N-Pr-i OPr

[0093] TABLE 33 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H CF₃N-Pr-i OBu-t CH₂Cl Me H H 0 H H CF₃ N-Pr-i OPh CH₂Cl Me H H 0 H H CF₃N-Pr-i OCH₂Ph CH₂Cl Me H H 0 H H CF₃ N-Pr-i OCH₂CH═CH₂ CH₂Cl Me H H 0 HH CF₃ N-Pr-i OCH(Me)CH═CH₂ CH₂Cl Me H H 0 H H CF₃ N-Pr-i OCH₂C≡CH CH₂ClMe H H 0 H H CF₃ N-Pr-i OCH(Me)C≡CH CH₂Cl Me H H 0 H H CF₃ N-Pr-i OCHF₂CH₂Cl Me H H 0 H H OCHF₂ N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-iOCH₂CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i OCH₂CHF₂ CH₂Cl Me H H 0 H HOCH₂CHF₂ N-Pr-i CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i SMe CH₂Cl Me H H 0 H HCF₃ N-Pr-i SOMe CH₂Cl Me H H 0 H H CF₃ N-Pr-i SO₂Me CH₂Cl Me H H 0 H HCF₃ N-Pr-i SEt CH₂Cl Me H H 0 H H CF₃ N-Pr-i SOEt CH₂Cl Me H H 0 H H CF₃N-Pr-i SO₂Et CH₂Cl Me H H 0 H H CF₃ N-Pr-i SPr-i CH₂Cl Me H H 0 H H CF₃N-Pr-i SOPr-i CH₂Cl Me H H 0 H H CF₃ N-Pr-i SO₂Pr-i CH₂Cl Me H H 0 H HCF₃ N-Pr-i SCF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i SOCF₃ CH₂Cl Me H H 0 H HCF₃ N-Pr-i SO₂CF₃ CH₂Cl Me H H 0 H H CF₃ N-Pr-i SCHF₂ CH₂Cl Me H H 0 H HCF₃ N-Pr-i SOCHF₂ CH₂Cl Me H H 0 H H CF₃ N-Pr-i SO₂CHF₂ CH₂Cl Me H H 0 HH CHF₃ N-Pr-i Cl CH₂Cl Me H H 0 H H CHF₂ N-Pr-i OMe CH₂Cl Me H H 0 H HCHF₂ N-Pr-i OCHF₂ CH₂Cl Me H H 0 H H CHF₃ N-Pr-i CN CH₂Cl Me H H 0 H HCHF₂ N-Pr-i Me CH₂Cl Me H H 0 H H Me N-Pr-i Cl CH₂Cl Me H H 0 H H MeN-Pr-i OMe CH₂Cl Me H H 0 H H Me N-Pr-i OCHF₂

[0094] TABLE 34 R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ CH₂Cl Me H H 0 H H MeN-Pr-i CN CH₂Cl Me H H 0 H H Me N-Pr-i Me CH₂Cl Me H H 0 H H Et N-Pr-iCl CH₂Cl Me H H 0 H H Et N-Pr-i OMe CH₂Cl Me H H 0 H H Et N-Pr-i OCHF₂CH₂Cl Me H H 0 H H Et N-Pr-i CN CH₂Cl Me H H 0 H H Et N-Pr-i Me CH₂Cl MeH H 0 H H OCHF₂ N-Pr-i Cl CH₂Cl Me H H 2 H H CF₃ N-Me Cl CHF₂ Me H H 2 HH CF₃ N-Me Cl CHClF Me H H 2 H H CF₃ N-Me Cl CHFMe Me H H 2 H H CF₃ N-MeCl CHClMe Me H H 2 H H CF₃ N-Me Cl CF₂Me Me H H 2 H H CF₃ N-Me ClCH₂CH₂F Me H H 2 H H CF₃ N-Me Cl CH₂CHF₂ Me H H 2 H H CF₃ N-Me ClCH₂CH₂Cl Me H H 2 H H CF₃ N-Me Cl CH₂CHCl₂ Me H H 2 H H CF₃ N-Me ClCH₂CClF₂ Me H H 2 H H CF₃ N-Me Cl CH₂CF₃ Me H H 2 H H CF₃ N-Me Cl CF₂CF₃Me H H 2 H H CF₃ N-Me Cl CH₂CH₂CF₃ Me H H 2 H H CF₃ N-Me Cl CH₂CH₂CHF₂Me H H 2 H H CF₃ N-Me Cl CF₂CF₂CF₃ Me H H 2 H H CF₃ N-Me Cl CH₂CF₂Me MeH H 2 H H CF₃ N-Me Cl CH₂CHFMe Me H H 2 H H CF₃ N-Me Cl CF₃ CF₃ H H 2 HH CF₃ N-Me Cl CHFPr-n Me H H 2 H H CF₃ N-Me Cl CF₂Pr-n Me H H 2 H H CF₃N-Me Cl CHCl₂ Me H H 0 H H CF₃ N-Me Cl CHF₂ Me H H 0 H H CF₃ N-Me ClCHClF Me H H 0 H H CF₃ N-Me Cl CHFMe Me H H 0 H H CF₃ N-Me Cl CHClMe MeH H 0 H H CF₃ N-Me Cl CF₂Me Me H H 0 H H CF₃ N-Me Cl

[0095] TABLE 35

R¹ R² R³ R⁴ n R⁵ R⁶ R¹⁵ Z² R¹⁶ 2-1153 CH₂CH₂F Me H H 0 H H CF₃ N-Me Cl2-1154 CH₂CHF₂ Me H H 0 H H CF₃ N-Me Cl 2-1155 CH₂CH₂Cl Me H H 0 H H CF₃N-Me Cl 2-1156 CH₂CHCl₂ Me H H 0 H H CF₃ N-Me Cl 2-1157 CH₂CClF₂ Me H H0 H H CF₃ N-Me Cl 2-1158 CH₂CF₃ Me H H 0 H H CF₃ N-Me Cl 2-1159 CF₂CF₃Me H H 0 H H CF₃ N-Me Cl 2-1160 CH₂CH₂CF₃ Me H H 0 H H CF₃ N-Me Cl2-1161 CH₂CH₂CHF₂ Me H H 0 H H CF₃ N-Me Cl 2-1162 CF₂CF₂CF₃ Me H H 0 H HCF₃ N-Me Cl 2-1163 CH₂CF₂Me Me H H 0 H H CF₃ N-Me Cl 2-1164 CH₂CHFMe MeH H 0 H H CF₃ N-Me Cl 2-1165 CF₃ CF₃ H H 0 H H CF₃ N-Me Cl 2-1166CHFPr-n Me H H 0 H H CF₃ N-Me Cl 2-1167 CF₂Pr-n Me H H 0 H H CF₃ N-Me Cl

[0096] TABLE 36

R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CH₂Cl Me H H 2 H H N-Me Cl H CH₂Cl Me H H2 H H N-Me Cl Me CH₂Cl Me H H 2 H H N-Me Cl Et CH₂Cl Me H H 2 H H N-MeCl CF₃ CH₂Cl Me H H 2 H H N-Me Cl Me CH₂Cl Me H H 2 H H N-Pr-i Cl MeCH₂Cl Me H H 2 H H N-Pr Cl Me CH₂Cl Me H H 2 H H N-Bu-t Cl Me CH₂Cl Me HH 2 H H N-CH₂Ph Cl Me CH₂Cl Me H H 2 H H N-Ph OMe Me CH₂Cl Me H H 2 H HN-Ph OEt Me CH₂Cl Me H H 2 H H N-Ph OCHF₂ Me CH₂Cl Me H H 2 H H N-PhOCH₂CF₃ Me CH₂Cl Me H H 2 H H N-Ph CF₃ H CH₂Cl Me H H 2 H H N-PhOCH₂CH═CH₂ Me CH₂Cl Me H H 2 H H N-Ph OCH₂C≡CH Me CH₂Cl Me H H 2 H HN-Ph Cl Me CH₂Cl Me H H 2 H H N-Ph(2-Cl) Cl Me CH₂Cl Me H H 2 H HN-Ph(2-F) Cl Me CH₂Cl Me H H 2 H H N-Ph(2-OMe) Cl Me CH₂Cl Me H H 2 H HN-Ph(2-Me) Cl Me CH₂Cl Me H H 2 H H N-Ph(3-Cl) Cl Me CH₂Cl Me H H 2 H HN-Ph(3-F) Cl Me CH₂Cl Me H H 2 H H N-Ph(3-OMe) Cl Me CH₂Cl Me H H 2 H HN-Ph(3-Me) Cl Me CH₂Cl Me H H 2 H H N-Ph(4-Cl) Cl Me CH₂Cl Me H H 2 H HN-Ph(4-F) Cl Me CH₂Cl Me H H 2 H H N-Ph(4-OMe) Cl Me CH₂Cl Me H H 2 H HN-Ph(4-Me) Cl Me

[0097] TABLE 37 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CH₂Br H H H 2 H H N-Ph ClMe CH₂Cl H H H 2 H H N-Ph Cl Me CH₂Cl H Me H 2 H H N-Ph Cl Me CH₂Cl Me HH 2 Me H N-Ph Cl Me CH₂Cl Me H H 2 Et H N-Ph Cl Me CH₂Cl Me H H 2 Pr-i HN-Ph Cl Me CH₂Cl Me H H 2 Me Me N-Ph Cl Me CH₂Cl Et H H 2 H H N-Ph Cl MeCH₂Cl CH₂Cl H H 2 H H N-Ph Cl Me CH₂Cl Pr-i H H 2 H H N-Ph Cl Me CH₂ClPr H H 2 H H N-Ph Cl Me CH₂Cl Pr-c H H 2 H H N-Ph Cl Me CH₂Cl CH₂Pr-c HH 2 H H N-Ph Cl Me CH₂F CH₂Cl H H 2 H H N-Ph Cl Me CH₂Br CH₂Cl H H 2 H HN-Ph Cl Me CH₂I CH₂Cl H H 2 H H N-Ph Cl Me CF₃ CH₂Cl H H 2 H H N-Ph ClMe CH₂Cl —(CH₂)3— H 2 H H N-Ph Cl Me CH₂Cl —(CH₂)4— H 2 H H N-Ph Cl MeCH₂Cl —(CH₂)5— H 2 H H N-Ph Cl Me CH₂Cl —(CH₂)6— H 2 H H N-Ph Cl MeCH₂Cl Me H H 1 H H N-Ph Cl H CH₂Cl Me H H 1 H H N-Ph Cl Me CH₂Cl Me H H1 H H N-Ph Cl Et CH₂Cl Me H H 1 H H N-Ph Cl CF₃ CH₂Cl Me H H 1 H H N-EtCl Me CH₂Cl Me H H 1 H H N-Pr-i Cl Me CH₂Cl Me H H 1 H H N-Pr Cl MeCH₂Cl Me H H 1 H H N-Bu-t Cl Me CH₂Cl Me H H 1 H H N-CH₂Ph Cl Me CH₂ClMe H H 1 H H N-Ph OMe Me CH₂Cl Me H H 1 H H N-Ph OEt Me CH₂Cl Me H H 1 HH N-Ph OCHF₂ Me

[0098] TABLE 38 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CH₂Cl Me H H 1 H H N-PhOCH₂CF₃ Me CH₂Cl Me H H 1 H H N-Ph CF₃ H CH₂Cl Me H H 1 H H N-PhOCH₂CH═CH₂ Me CH₂Cl Me H H 1 H H N-Ph OCH₂C≡CH Me CH₂Cl Me H H 1 H HN-Ph Cl Me CH₂Cl Me H H 1 H H N-Ph(2—Cl) Cl Me CH₂Cl Me H H 1 H HN-Ph(2—F) Cl Me CH₂Cl Me H H 1 H H N-Ph(2—OMe) Cl Me CH₂Cl Me H H 1 H HN-Ph(2-Me) Cl Me CH₂Cl Me H H 1 H H N-Ph(3—Cl) Cl Me CH₂Cl Me H H 1 H HN-Ph(3—F) Cl Me CH₂Cl Me H H 1 H H N-Ph(3—OMe) Cl Me CH₂Cl Me H H 1 H HN-Ph(3-Me) Cl Me CH₂Cl Me H H 1 H H N-Ph(4—Cl) Cl Me CH₂Cl Me H H 1 H HN-Ph(4—F) Cl Me CH₂Cl Me H H 1 H H N-Ph(4—OMe) Cl Me CH₂Cl Me H H 1 H HN-Ph(4-Me) Cl Me CH₂Br H H H 1 H H N-Ph Cl Me CH₂Cl H H H 1 H H N-Ph ClMe CH₂Cl H Me H 1 H H N-Ph Cl Me CH₂Cl Me H H 1 Me H N-Ph Cl Me CH₂Cl MeH H 1 Et H N-Ph Cl Me CH₂Cl Me H H 1 Pr-i H N-Ph Cl Me CH₂Cl Me H H 1 MeMe N-Ph Cl Me CH₂Cl Et H H 1 H H N-Ph Cl Me CH₂Cl CH₂Cl H H 1 H H N-PhCl Me CH₂Cl Pr-i H H 1 H H N-Ph Cl Me CH₂Cl Pr H H 1 H H N-Ph Cl MeCH₂Cl Pr-c H H 1 H H N-Ph Cl Me CH₂Cl CH₂Pr-c H H 1 H H N-Ph Cl Me CH₂FCH₂Cl H H 1 H H N-Ph Cl Me CH₂Br CH₂Cl H H 1 H H N-Ph Cl Me CH₂I CH₂Cl HH 1 H H N-Ph Cl Me

[0099] TABLE 39 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CF₃ CH₂Cl H H 1 H H N-PhCl Me CH₂Cl —(CH₂)₃— H 1 H H N-Ph Cl Me CH₂Cl —(CH₂)₄— H 1 H H N-Ph ClMe CH₂Cl —(CH₂)₅— H 1 H H N-Ph Cl Me CH₂Cl —(CH₂)₆— H 1 H H N-Ph Cl MeCH₂Cl Me H H 0 H H N-Me Cl H CH₂Cl Me H H 0 H H N-Me Cl Me CH₂Cl Me H H0 H H N-Me Cl Et CH₂Cl Me H H 0 H H N-Me Cl CF₃ CH₂Cl Me H H 0 H H N-EtCl Me CH₂Cl Me H H 0 H H N-Pr-i Cl Me CH₂Cl Me H H 0 H H N-Pr Cl MeCH₂Cl Me H H 0 H H N-Bu-t Cl Me CH₂Cl Me H H 0 H H N-CH2Ph Cl Me CH₂ClMe H H 0 H H N-Ph OMe Me CH₂Cl Me H H 0 H H N-Ph OEt Me CH₂Cl Me H H 0 HH N-Ph OCHF₂ Me CH₂Cl Me H H 0 H H N-Ph OCH₂CF₃ Me CH₂Cl Me H H 0 H HN-Ph CF₃ H CH₂Cl Me H H 0 H H N-Ph OCH₂CH═CH₂ Me CH₂Cl Me H H 0 H H N-PhOCH₂C≡CH Me CH₂Cl Me H H 0 H H N-Ph Cl Me CH₂Cl Me H H 0 H H N-Ph(2—Cl)Cl Me CH₂Cl Me H H 0 H H N-Ph(2—F) Cl Me CH₂Cl Me H H 0 H H N-Ph(2—OMe)Cl Me CH₂Cl Me H H 0 H H N-Ph(2-Me) Cl Me CH₂Cl Me H H 0 H H N-Ph(3—Cl)Cl Me CH₂Cl Me H H 0 H H N-Ph(3—F) Cl Me CH₂Cl Me H H 0 H H N-Ph(3—OMe)Cl Me CH₂Cl Me H H 0 H H N-Ph(3-Me) Cl Me CH₂Cl Me H H 0 H H N-Ph(4—Cl)Cl Me CH₂Cl Me H H 0 H H N-Ph(4—F) Cl Me CH₂Cl Me H H 0 H H N-Ph(4—OMe)Cl Me

[0100] TABLE 40 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CH₂Cl Me H H 0 H HN-Ph(4-Me) Cl Me CH₂Cl H H H 0 H H N-Ph Cl Me CH₂Cl H H H 0 H H N-Ph ClMe CH₂Cl H Me H 0 H H N-Ph Cl Me CH₂Cl Me H H 0 Me H N-Ph Cl Me CH₂Cl MeH H 0 Et H N-Ph Cl Me CH₂Cl Me H H 0 Pr-i H N-Ph Cl Me CH₂Cl Me H H 0 MeMe N-Ph Cl Me CH₂Cl Et H H 0 H H N-Ph Cl Me CH₂Cl CH₂Cl H H 0 H H N-PhCl Me CH₂Cl Pr-i H H 0 H H N-Ph Cl Me CH₂Cl Pr H H 0 H H N-Ph Cl MeCH₂Cl Pr-c H H 0 H H N-Ph Cl Me CH₂Cl CH₂Pr-c H H 0 H H N-Ph Cl Me CH₂FCH₂Cl H H 0 H H N-Ph Cl Me CH₂Br CH₂Cl H H 0 H H N-Ph Cl Me CH₂I CH₂Cl HH 0 H H N-Ph Cl Me CF₃ CH₂Cl H H 0 H H N-Ph Cl Me CH₂Cl —(CH₂)₃— H 0 H HN-Ph Cl Me CH₂Cl —(CH₂)₄— H 0 H H N-Ph Cl Me CH₂Cl —(CH₂)₅— H 0 H H N-PhCl Me CH₂Cl —(CH₂)₆— H 0 H H N-Ph Cl Me CH₂Cl Et H H 2 H H N-H H H CH₂ClMe H H 2 H H N-H CF₃ H CH₂Cl Me H H 2 H H N-CHF₂ COMe H CH₂Cl Me H H 2 HH N-CHF₂ COMe Me CH₂Cl Me H H 2 H H N-CHF₂ COOMe H CH₂Cl Me H H 2 H HN-CHF₂ COOMe Me CH₂Cl Me H H 2 H H N-CHF₂ OCHF₂ H CH₂Cl Me H H 2 H HN-CHF₂ OCHF₂ Me CH₂Cl Me H H 2 H H N-CHF₂ OCHF₂ Et CH₂Cl Me H H 2 H HN-CHF₂ CF₃ H CH₂Cl Me H H 2 H H N-CHF₂ CF₃ Me

[0101] TABLE 41 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁴ R¹⁸ R¹⁹ CH₂Cl Me H H 2 H H N-CHF₂CF₃ Et CH₂Cl Me H H 2 H H N-CHF₂ —(CH₂)₃— CHCl₂ Me H H 2 H H N-Me CF₃ HCHF₂ Me H H 2 H H N-Me CF₃ H CHClF Me H H 2 H H N-Me CF₃ H CHFMe Me H H2 H H N-Me CF₃ H CHClMe Me H H 2 H H N-Me CF₃ H CF₂Me Me H H 2 H H N-MeCF₃ H CH₂CH₂F Me H H 2 H H N-Me CF₃ H CH₂CHF₂ Me H H 2 H H N-Me CF₃ HCH₂CH₂Cl Me H H 2 H H N-Me CF₃ H CH₂CHCl₂ Me H H 2 H H N-Me CF₃ HCH₂CClF₂ Me H H 2 H H N-Me CF₃ H CH₂CF₃ Me H H 2 H H N-Me CF₃ H CF₂CF₃Me H H 2 H H N-Me CF₃ H CH₂CH₂CF₃ Me H H 2 H H N-Me CF₃ H CH₂CH₂CHF₂ MeH H 2 H H N-Me CF₃ H CF₂CF₂CF₃ Me H H 2 H H N-Me CF₃ H CH₂CF₂Me Me H H 2H H N-Me CF₃ H CH₂CHFMe Me H H 2 H H N-Me CF₃ H CF₃ CF₃ H H 2 H H N-MeCF₃ H CHFPr-n Me H H 2 H H N-Me CF₃ H CF₂Pr-n Me H H 2 H H N-Me CF₃ H

[0102] TABLE 42

R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R²⁰ R²¹ CH₂Cl Me H H 2 H H N-Me H OMe CH₂Cl Me HH 2 H H N-Me H OEt CH₂Cl Me H H 2 H H N-Me H OCHF₂ CH₂Cl Me H H 2 H HN-Me H OCH₂CF₃ CH₂Cl Me H H 2 H H N-Ph H OMe CH₂Cl Me H H 2 H H N-Ph HOEt CH₂Cl Me H H 2 H H N-Ph H OCHF₂ CH₂Cl Me H H 2 H H N-Ph H OCH₂CF₃CH₂Cl Me H H 2 H H S Me H CH₂Cl CH₂Cl H H 2 H H N-Ph H OMe CH₂Cl H H H 2H H N-Ph H OEt CH₂Cl H Me H 2 H H N-Ph H OMe CH₂Cl Me H H 2 Me H N-Ph HOEt CH₂Cl Me H H 2 Et H N-Ph H OMe CH₂Cl Me H H 2 Pr-i H N-Ph H OEtCH₂Cl Me H H 2 Me Me N-Ph H OMe CH₂Cl Et H H 2 H H N-Ph H OEt CH₂ClCH₂Br H H 2 H H N-Ph H OMe CH₂Cl Pr-i H H 2 H H N-Ph H OEt CH₂Cl Pr H H2 H H N-Ph H OMe CH₂Cl Pr-c H H 2 H H N-Ph H OEt CH₂Cl CH₂Pr-c H H 2 H HN-Ph H OMe CH₂Br Me H H 2 H H N-Ph H OEt CH₂F Me H H 2 H H N-Ph H OMeCH₂I Me H H 2 H H N-Ph H OEt CF₃ Me H H 2 H H N-Ph H OMe CH₂Cl —(CH₂)₃—H 2 H H N-Ph H OEt CH₂Cl —(CH₂)₄— H 2 H H N-Ph H OMe CH₂Cl —(CH₂)₅— H 2H H N-Ph H OMe CH₂Cl —(CH₂)₆— H 2 H H N-Ph H OEt CH₂Cl Me H H 1 H H N-MeH OMe

[0103] TABLE 43 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R²⁰ R²¹ CH₂Cl Me H H 1 H H N-Me HOEt CH₂Cl Me H H 1 H H N-Me H OCHF₂ CH₂Cl Me H H 1 H H N-Me H OCH₂CF₃CH₂Cl Me H H 1 H H N-Ph H OMe CH₂Cl Me H H 1 H H N-Ph H OEt CH₂Cl Me H H1 H H N-Ph H OCHF₂ CH₂Cl Me H H 1 H H N-Ph H OCH₂CF₃ CH₂Cl Me H H 1 H HS Me H CH₂Cl CH₂Cl H H 1 H H N-Ph H OMe CH₂Cl H H H 1 H H N-Ph H OEtCH₂Cl H Me H 1 H H N-Ph H OMe CH₂Cl Me H H 1 Me H N-Ph H OEt CH₂Cl Me HH 1 Et H N-Ph H OMe CH₂Cl Me H H 1 Pr-i H N-Ph H OEt CH₂Cl Me H H 1 MeMe N-Ph H OMe CH₂Cl Et H H 1 H H N-Ph H OEt CH₂Cl CH₂Br H H 1 H H N-Ph HOMe CH₂Cl Pr-i H H 1 H H N-Ph H OEt CH₂Cl Pr H H 1 H H N-Ph H OMe CH₂ClPr-c H H 1 H H N-Ph H OEt CH₂Cl CH₂Pr-c H H 1 H H N-Ph H OMe CH₂Br Me HH 1 H H N-Ph H OEt CH₂F Me H H 1 H H N-Ph H OMe CH₂Cl Me H H 1 H H N-PhH OEt CH₂Cl Me H H 1 H H N-Ph H OMe CH₂Cl —(CH₂)₃— H 1 H H N-Ph H OEtCH₂Cl —(CH₂)₄— H 1 H H N-Ph H OMe CH₂Cl —(CH₂)₅— H 1 H H N-Ph H OMeCH₂Cl —(CH₂)₆— H 1 H H N-Ph H OEt CH₂Cl Me H H 0 H H N-Me H OMe CH₂Cl MeH H 0 H H N-Me H OEt CH₂Cl Me H H 0 H H N-Me H OCHF₂ CH₂Cl Me H H 0 H HN-Me H OCH₂CF₃ CH₂Cl Me H H 0 H H N-Ph H OMe

[0104] TABLE 44 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R²⁰ R²¹ CH₂Cl Me H H 0 H H N-Ph HOEt CH₂Cl Me H H 0 H H N-Ph H OCHF₂ CH₂Cl Me H H 0 H H N-Ph H OCH₂CF₃CH₂Cl Me H H O H H S Me H CH₂Cl CH₂Cl H H 0 H H N-Ph H OMe CH₂Cl H H H 0H H N-Ph H OEt CH₂Cl H Me H 0 H H N-Ph H OMe CH₂Cl Me H H 0 Me H N-Ph HOEt CH₂Cl Me H H 0 Et H N-Ph H OMe CH₂Cl Me H H 0 Pr-i H N-Ph H OEtCH₂Cl Me H H 0 Me Me N-Ph H OMe CH₂Cl Et H H 0 H H N-Ph H OEt CH₂ClCH₂Br H H 0 H H N-Ph H OMe CH₂Cl Pr-i H H 0 H H N-Ph H OEt CH₂Cl Pr H H0 H H N-Ph H OMe CH₂Cl Pr-c H H 0 H H N-Ph H OEt CH₂Cl CH₂Pr-c H H 0 H HN-Ph H OMe CH₂Br Me H H 0 H H N-Ph H OEt CH₂F Me H H 0 H H N-Ph H OMeCH₂I Me H H 0 H H N-Ph H OEt CF₃ Me H H 0 H H N-Ph H OMe CH₂Cl —(CH₂)₃—H 0 H H N-Ph H OEt CH₂Cl —(CH₂)₄— H 0 H H N-Ph H OMe CH₂Cl —(CH₂)₅— H 0H H N-Ph H OMe CH₂Cl —(CH₂)₆— H 0 H H N-Ph H OEt CH₂Cl Et H H 2 H H S HH CH₂Cl Et H H 2 H H N-H H H CH₂Cl Me H H 2 H H N-Me Cl CHF₂ CH₂Cl Me HH 2 H H N-Me Cl CF₃ CH₂Cl Me H H 2 H H N-Me Cl CF₃ CHF₂ Me H H 2 H HN-Me Cl CF₃ CHClF Me H H 2 H H N-Me Cl CF₃ CHFMe Me H H 2 H H N-Me ClCF₃

[0105] TABLE 45 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R²⁰ R²¹ CHClMe Me H H 2 H H N—MeCl CF₃ CF₂Me Me H H 2 H H N—Me Cl CF₃ CH₂CH₂F Me H H 2 H H N—Me Cl CF₃CH₂CHF₂ Me H H 2 H H N—Me Cl CF₃ CH₂CH₂Cl Me H H 2 H H N—Me Cl CF₃CH₂CHCl₂ Me H H 2 H H N—Me Cl CF₃ CH₂CClF₂ Me H H 2 H H N—Me Cl CF₃CH₂CF₃ Me H H 2 H H N—Me Cl CF₃ CF₂CF₃ Me H H 2 H H N—Me Cl CF₃CH₂CH₂CF₃ Me H H 2 H H N—Me Cl CF₃ CH₂CH₂CHF₂ Me H H 2 H H N—Me Cl CF₃CF₂CF₂CF₃ Me H H 2 H H N—Me Cl CF₃ CH₂CF₂Me Me H H 2 H H N—Me Cl CF₃CH₂CHFMe Me H H 2 H H N—Me Cl CF₃ CF₃ CF₃ H H 2 H H N—Me Cl CF₃ CHFPr-nMe H H 2 H H N—Me Cl CF₃ CF₂Pr-n Me H H 2 H H N—Me Cl CF₃ CH₂Cl Me H H 0H H N—Me Cl CHF₃ CH₂Cl Me H H 0 H H N—Me Cl CF₃ CHCl₂ Me H H 0 H H N—MeCl CF₃ CHF₂ Me H H 0 H H N—Me Cl CF₃ CHClF Me H H 0 H H N—Me Cl CF₃CHFMe Me H H 0 H H N—Me Cl CF₃ CHClMe Me H H 0 H H N—Me Cl CF₃ CF₂Me MeH H 0 H H N—Me Cl CF₃ CH₂CH₂F Me H H 0 H H N—Me Cl CF₃ CH₂CHF₂ Me H H 0H H N—Me Cl CF₃ CH₂CH₂Cl Me H H 0 H H N—Me Cl CF₃ CH₂CHCl₂ Me H H 0 H HN—Me Cl CF₃ CH₂CClF₂ Me H H 0 H H N—Me Cl CF₃ CH₂CF₃ Me H H 0 H H N—MeCl CF₃ CF₂CF₃ Me H H 0 H H N—Me Cl CF₃ CH₂CH₂CF₃ Me H H 0 H H N—Me ClCF₃

[0106] TABLE 46 R¹ R² R³ R⁴ n R⁵ R⁶ Z⁵ R²⁰ R²¹ CH₂CH₂CHF₂ Me H H 0 H HN—Me Cl CF₃ CF₂CF₂CF₃ Me H H 0 H H N—Me Cl CF₃ CH₂CF₂Me Me H H 0 H HN—Me Cl CF₃ CH₂CHFMe Me H H 0 H H N—Me Cl CF₃ CF₃ CF₃ H H 0 H H N—Me ClCF₃ CHFPr-n Me H H 0 H H N—Me Cl CF₃ CF₂Pr-n Me H H 0 H H N—Me Cl CF₃

[0107] TABLE 47

R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 2 H H 1,2,4-Oxadiazol-3-yl CH₂Cl MeH H 2 H H 3-Phenyl-1,2,4-oxadiazol-5-yl CH₂Cl Me H H 2 H H3-Benzyl-1,2,4-oxadiazol-5-yl CH₂Cl Me H H 2 Pr-i H4-Trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4,6-Dimetoxypyrimidin-2-yl CH₂Cl Me H H 2 H H 4,6-Dichloropyrimidin-5-ylCH₂Cl Me H H 2 H H 1,4-Dimethylimidazol-5-yl CH₂Cl Me H H 2 H H1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl CH₂Cl Me H H 2 H H4-Methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Chloro-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Phenoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Phenyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Chloro-6-methylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Chloro-6-methoxypyrimidin-5-yl CH₂Cl Me H H 2 H H4,6-Dimethoxypyrimidin-5-yl CH₂Cl Me H H 2 H H4,6-Diethoxypyrimidin-5-yl CH₂Cl Me H H 2 H H4,6-Dimethoxypyrimidin-2-yl CH₂Cl Me H H 2 H H4,6-Diethoxypyrimidin-2-yl CH₂Cl H H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl H H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl H Me H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 Me H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 Et H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 Pr-i H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 Me Me4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-i H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl

[0108] TABLE 48 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Pr H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-c H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl CH₂Pr-c H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Br Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂F Me H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂I Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₃ Me H H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₃— H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₄— H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₅— H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₆— H 2 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H HPyridin-2-yl CH₂Cl Me H H 1 H H 1,2,4-Oxadiazol-3-yl CH₂Cl Me H H 1 H H3-Phenyl-1,2,4-oxadiazol-5-yl CH₂Cl Me H H 1 H H3-Benzyl-1,2,4-oxadiazol-5-yl CH₂Cl Me H H 1 Pr-i H4-Trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4,6-Dichloropyrimidin-5-yl CH₂Cl Me H H 1 H H 1,4-Dimethylimidazol-5-ylCH₂Cl Me H H 1 H H 1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl CH₂ClMe H H 1 H H 4-Methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Chloro-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Ethoxy-6-trifluoromrthylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Phenoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Phenyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Chloro-6-methylpyrimidin-5-yl CH₂Cl Me H H 1 H H4-Chloro-6-methoxyrimidin-5-yl CH₂Cl Me H H 1 H H4,6-Dimethoxypyrimidin-5-yl CH₂Cl Me H H 1 H H4,6-Diethoxypyrimidin-5-yl CH₂Cl Me H H 1 H H4,6-Dimethoxypyrimidin-2-yl CH₂Cl Me H H 1 H H4,6-Diethoxypyrimidin-2-yl CH₂Cl H H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl H H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidun-5-yl CH₂Cl H Me H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl

[0109] TABLE 49 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 1 Me H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 Et H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 Pr-i H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 1 Me Me4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-i H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-c H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl CH₂Pr-c H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Br Me H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂F Me H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂I Me H H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₃ Me H H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₃— H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₄— H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₅— H 1 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₆— H 1 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H1,2,4-Oxadiazol-3-yl CH₂Cl Me H H 0 H H 3-Phenyl-1,2,4-oxadiazol-5-ylCH₂Cl Me H H 0 H H 3-Benzyl-1,2,4-oxadiazol-5-yl CH₂Cl Me H H 0 Pr-i H4-Trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4,6-Dichloropyrimidin-5-yl CH₂Cl Me H H 0 H H 2,4-Diphenylpyridin-3-ylCH₂Cl Me H H 0 H H 1,4-Dimethylimidazol-5-yl CH₂Cl Me H H 0 H H1-Phenyl-4-methoxycarbonyl-1,2,3-triazol-5-yl CH₂Cl Me H H 0 H H4-Methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Chloro-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Phenoxy-6-trifluoromethylpyrimidin-5-yl

[0110] TABLE 50 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 0 H H4-Phenyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Chloro-6-methylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Chloro-6-methoxypyrimidin-5-yl CH₂Cl Me H H 0 H H4,6-Dimethoxypyrimidin-5-yl CH₂Cl Me H H 0 H H4,6-Diethoxypyrimidin-5-yl CH₂Cl Me H H 0 H H4,6-Dimethoxypyrimidin-2-yl CH₂Cl Me H H 0 H H4,6-Diethoxypyrimidin-2-yl CH₂Cl H H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl H H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl H Me H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 Me H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 Et H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 Pr-i H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 Me Me4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Et H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-i H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Pr-c H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl CH₂Pr-c H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Br Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂F Me H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂I Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₃ Me H H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₃— H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₄— H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₅— H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl —(CH₂)₆— H 0 H H4-Methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl CH₂Cl H H 2 H HPyrrol-1-yl CH₂Cl CH₂Cl H H 2 H H Oxazol-2-yl CH₂Cl CH₂Br H H 2 H H1H-Imidazol-2-yl CH₂Cl CF₃ H H 2 H H 1H-Imidazol-4-yl CH₂Cl CH₂Cl H H 2H H 1H-Imidazol-5-yl CH₂Cl CH₂Cl H H 2 H H 1H-1,3,4-Triazol-2-yl

[0111] TABLE 51 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl CH₂Cl H H 2 H H1H-1,3,4-Triazol-5-yl CH₂Cl Me H H 2 H H4-iso-Propoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Difluoromethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Methoxy-2-methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Ethoxy-2-methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H2,4-Dimethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H2,4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H2-Amino-4-methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H2-Amino-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Methoxy-2-methylthio-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 HH 4-Ethoxy-2-methylthio-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 HH 4-Methoxy-2-methylsulfonyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me HH 2 H H 4-Ethoxy-2-methylsulfonyl-6-trifluoromethylpyrimidin-5-yl CH₂ClMe H H 2 H H 2-Difluoromethoxy-4-methoxy-6-trifluoromethylpyrimidin-5-ylCH₂Cl Me H H 2 H H2-Difluoromethoxy-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H2 H H 2-Cyano-4-methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 HH 2-Cyano-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 H H4-Methoxy-2-methylamino-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2 HH 4-Ethoxy-2-methylamino-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 2H H 2-Dimethylamino-4-methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me HH 2 H H 2-Dimethylamino-4-ethoxy-6-trifluoromethylpyrimidin-5-yl

[0112] TABLE 52 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 2 H H4-Cyano6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-iso-Propaxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Difluoromethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Methoxy-2-methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Ethoxy-2-methyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H2,4-Dimethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H2,4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H2-Amino-4-methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H2-Amino-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Methoxy-2-methylthio-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 HH 4-Ethoxy-2-methylthio-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 HH 4-Methoxy-2-methylsulfonyl-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me HH 0 H H 4-Ethoxy-2-methylsulfonyl-6-trifluoromethylpyrimidin-5-yl CH₂ClMe H H 0 H H 2-Difluoromethoxy-4-methoxy-6-trifluoromethylpyrimidin-5-ylCH₂Cl Me H H 0 H H2-Difluoromethoxy-4-ethoxy-6-trilluoromethylpyrimidin-5-yl CH₂Cl Me H H0 H H 2-Cyano-4-methoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 HH 2-Cyano-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 H H4-Methoxy-2-methylamino-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0 HH 4-Ethoxy-2-methylamino-6-trifluoromethylpynmidin-5-yl CH₂Cl Me H H 0 HH 2-Dimethylamino-4-methoxy-6-trifluoromethylpyrimidin-5-yl

[0113] TABLE 53 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 0 H H2-Dimethylamino-4-ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂Cl Me H H 0H H 4-Cyano6-trifluoromethylpyrimidin-5-yl CHCl₂ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHF₂ Me H H 2 H H4-Ethoxy-6-trilluoromethylpyrimidin-5-yl CHClF Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHFMe Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHClMe Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂Me Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂F Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CHF₂ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂Cl Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CHCl₂ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CClF₂ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CF₃ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂CF₃ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂CF₃ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂CHF Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂CF₂CF₃ Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CF₂Me Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CHFMe Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₃ CF₃ H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHFPr-n Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂Pr-n Me H H 2 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHCl₂ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHF₂ Me H H 0 H H4-Ethoxy-6-trilluoromethylpyrimidin-5-yl CHClF Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHFMe Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHClMe Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂Me Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂F Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CHF₂ Me H H 0 H H4-Ethoxy-6-trilluoromethylpyrimidin-5-yl CH₂CH₂Cl Me H H 0 H H4-Ethoxy-6-trilluoromethylpyrimidin-5-yl CH₂CHCl₂ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CClF₂ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl

[0114] TABLE 54 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂CF₃ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂CF₃ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yI CH₂CH₂CF₃ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CH₂CHF Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂CF₂CF₃ Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CF₂Me Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CH₂CHFMe Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₃ CF₃ H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CHFPr-n Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl CF₂Pr-n Me H H 0 H H4-Ethoxy-6-trifluoromethylpyrimidin-5-yl

[0115] TABLE 55

R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 2 H H Benzimidazol-2-yl CH₂Cl Me H H2 H H Benzothiophen-2-yl CH₂Cl Me H H 2 H H 3-Chlorobenzothiophen-2-ylCH₂Cl Me H H 2 H H Benzotriazol-1-yl CH₂Cl Me H H 2 H H1-Methylindazol-4-yl CH₂Cl Me H H 2 H H Benzoxazol-2-yl CH₂Cl Me H H 2 HH 3-Methylbenzothiophen-2-yl CH₂Cl Me H H 2 H H3-Bromobenzothiophen-2-yl CH₂Cl Me H H 2 H H Benzothiophen-7-yl CF₃ Me HH 2 H H Benzothiophen-7-yl CH₂F Me H H 2 H H Benzothiophen-7-yl CH₂Cl MeH H 2 H H 1-Methylindazol-7-yl CH₂Cl Me H H 2 H H3-Chloro-1-methylindol-2-yl CH₂Cl Me H H 1 H H Benzimidazol-2-yl CH₂ClMe H H 1 H H Benzothiophen-2-yl CH₂Cl Me H H 1 H H3-Chlorobenzothiophen-2-yl CH₂Cl Me H H 1 H H Benzotriazol-1-yl CH₂Cl MeH H 1 H H 1-Methylindazol-4-yl CH₂Cl Me H H 1 H H Benzothiophen-3-ylCH₂Cl Me H H 1 H H 5-Chlorobenzothiophen-3-yl CH₂Cl Me H H 1 H HBenzoxazol-2-yl CH₂Cl Me H H 1 H H 3-Methylbenzothiophen-2-yl CH₂Cl Me HH 1 H H 3-Bromobenzothiophen-2-yl CH₂Br Me H H 1 H H Benzothiophen-7-ylCF₃ Me H H 1 H H Benzothiophen-7-yl CH₂F Me H H 1 H H Benzothiophen-7-ylCH₂Cl Me H H 1 H H Benzothiophen-7-yl CH₂Cl Me H H 1 H H1-Methylindazol-7-yl

[0116] TABLE 56 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 1 H H3-Chloro-1-methylindol-2-yl CH₂Cl Me H H 0 H H Benzimidazol-2-yl CH₂ClMe H H 0 H H Benzothiophen-2-yl CH₂Cl Me H H 0 H H3-Chlorobenzothiophen-2-yl CH₂Cl Me H H 0 H H Benzotriazol-1-yl CH₂Cl MeH H 0 H H 1-Methylindazol-4-yl CH₂Cl Me H H 0 H H Benzothiophen-3-ylCH₂Cl Me H H 0 H H 5-Chlorobenzothiophen-3-yl CH₂Cl Me H H 0 H HBenzoxazol-2-yl CH₂Cl Me H H 0 H H 3-Methylbenzothiophen-2-yl CH₂Cl Me HH 0 H H 3-Bromobenzothiophen-2-yl CH₂Br Me H H 0 H H Benzothiophen-7-ylCF₃ Me H H 0 H H Benzothiophen-7-yl CH₂F Me H H 0 H H Benzothiophen-7-ylCH₂Cl Me H H 0 H H Benzothiophen-7-yl CH₂Cl Me H H 0 H H1-Methylindazol-7-yl CH₂Cl Me H H 0 H H 3-Chloro-1-methylindol-2-ylCH₂Cl Pr-c H H 2 H H Benzoxazol-2-yl CH₂Cl Me H H 2 H H4-Chlorobenzoxazol-2-yl CH₂Cl Me H H 2 H H 5-Chlorobenzoxazol-2-yl CH₂ClMe H H 2 H H 6-Chlorobenzoxazol-2-yl CH₂Cl Me H H 2 H H7-Chlorobenzoxazol-2-yl CH₂Cl Me H H 2 H H 4-Fluorobenzoxazol-2-yl CH₂ClMe H H 2 H H 5-Fluorobenzaxazol-2-yl CH₂Cl Me H H 2 H H6-Fluorobenzoxazol-2-yl CH₂Cl Me H H 2 H H 7-Fluorobenzoxazol-2-yl CH₂ClCH₂Pr-c H H 2 H H 4-Methylbenzoxazol-2-yl CH₂Cl Me H H 2 H H5-Methylbenzoxazol-2-yl CH₂Cl Me H H 2 H H 6-Methylbenzoxazol-2-yl CH₂ClMe H H 2 H H 7-Methylbenzoxazol-2-yl CH₂Cl Me H H 2 H H4-Methoxybenzoxazol-2-yl CH₂Cl Me H H 2 H H 5-Methoxybenzoxazol-2-ylCH₂Cl Me H H 2 H H 6-Methoxybenzoxazol-2-yl

[0117] TABLE 57 R¹ R² R³ R⁴ n R⁵ R⁶ Y¹ CH₂Cl Me H H 2 H H7-Methoxybenzoxazol-2-yl CH₂Cl Me H H 2 H H Quinolin-2-yl CH₂Cl CH₂Cl HH 2 H H Quinolin-6-yl CH₂Cl Me H H 2 H H Quinolin-2-yl

[0118] The compound of the present invention having the general formula[I] can be produced by the processes shown below. However, theproduction is not restricted to these processes alone.

PRODUCTION PROCESS 1

[0119] (Step 1 to Step 5)

[0120] wherein R¹, R², R³, R⁴, R⁵, R⁶ and Y have the same meanings asgiven above; X¹ is a halogen atom; R⁷ is a C1 to C4 alkyl group, anoptionally substituted phenyl group or an optionally substituted benzylgroup; L is an eliminatable group such as halogen atom, C1 to C4alkylsulfonyl group, optionally substituted phenylsulfonyl group,optionally substituted benzylsulfonyl group or the like; and x is anumber of 1 or 10 more.

[0121] The individual steps of the above production process aredescribed in detail below.

[0122] (Step 1)

[0123] A sulfide derivative represented by the general formula [5] canbe produced by reacting a compound represented by the genera formula [1]with a sodium hydrosulfide hydrate represented by the general formula[2] in a solvent or in the absence of a solvent (preferably in anappropriate solvent) in the presence or absence of a base to produce amercaptan salt represented by the general formula [3] in the reactionsystem and then reacting the mercaptan salt [3] with a halogenderivative represented by the general formula [4] without isolating themercaptan salt [3] {optionally, a radical generator [e.g. Rongalit(trade name) , CH₂(OH)SO₂Na.2H₂O] may be added}.

[0124] The reaction temperature in each reaction is any temperatureranging from 0° C. to the reflux temperature in reaction system,preferably a temperature range of 0° C. to 100° C. The reaction time is0.5 to 24 hours although it differs depending upon the compounds used.

[0125] With respect to the amounts of the reagents used in thereactions, the amounts of the compound represented by the generalformula [2] and the compound represented by the general formula [4] areeach 1 to 3 equivalents relative to 1 equivalent of the compoundrepresented by the general formula [1]; and when a base is used, theamount of the base is 0.5 to 3 equivalents.

[0126] As the solvent used, there can be mentioned, for example, etherssuch as dioxane, tetrahydrofuran (THF) and the like; halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethylsulfoxide, (DMSO), sulfolane and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol and the like;ketones such as acetone, 2-butanone and the like; nitriles such asacetonitrile and the like; water; and mixtures thereof.

[0127] As the base used, there can be mentioned, for example, metalhydrides such as sodium hydride and the like; alkali metal amides suchas sodium amide, lithium diisopropylamide and the like; organic basessuch as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene andthe like; alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and the like; alkaline earth metal hydroxides such as calciumhydroxide, magnesium hydroxide and the like; alkali metal carbonatessuch as sodium carbonate, potassium carbonate and the like; alkali metalbicarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like (inorganic bases); and metal alcoholates such assodium methoxide, sodium ethoxide, potassium tertbutoxide and the like.

[0128] (Step 2)

[0129] A sulfoxide derivative represented by the general formula [6] canbe produced by reacting the sulfide derivative represented by thegeneral formula [5] with an oxidizing agent in an appropriate solvent inthe presence or absence of a catalyst.

[0130] The reaction temperature is any temperature ranging from 0° C. tothe reflux temperature in reaction system, preferably a temperaturerange of 0°0 C. to 60° C. The reaction time is 1 to 72 hours although itdiffers depending upon the compounds used.

[0131] With respect to the amounts of the reagents used in the reaction,the amount of the oxidizing agent is 1 to 3 equivalents relative to 1equivalent of the compound represented by the general formula [5] and,when the catalyst is used, the amount of the catalyst is 0.01 to 0.5equivalent.

[0132] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloromethane, chloroform,dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene andthe like; ethers such as dioxane, tetrahydrofuran (THF),dimethoxyethane, diethyl ether and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidinone and the like; alcohols such as methanolethanol, propanol, isopropanol, butanol, tert-butanol and the like;ketones such as acetone, 2-butanone and the like; nitrites such asacetonitrile and the like; acetic acid; water; and mixtures thereof.

[0133] As the oxidizing agent used, there can be mentioned, for example,organic peroxides such as m-chloroperbenzoic acid, hydrogen peroxide,performic acid, peracetic acid and the like; and inorganic peroxidessuch as potassium permanganate, sodium periodate and the like.

[0134] As the catalyst used, there can be mentioned, for example, metalcatalysts such as sodium tungstate and the like.

[0135] (Step 3)

[0136] A sulfone derivative represented by the general formula [7] canbe produced by reacting the sulfoxide derivative represented by thegeneral formula [6] with an oxidizing agent in an appropriate solvent inthe presence or absence of a catalyst.

[0137] The reaction temperature is any temperature ranging from 0° C. tothe reflux temperature in reaction system, preferably a temperaturerange of 0° C. to 60° C. The reaction time is 1 to 72 hours although itdiffers depending upon the compounds used.

[0138] With respect to the amounts of the reagents used in the reaction,the amount of the oxidizing agent is 1 to 3 equivalents relative to 1equivalent of the compound represented by the general formula [6] and,when the catalyst is used, the amount of the catalyst is 0.01 to 0.5equivalent.

[0139] The solvent, oxidizing agent and catalyst used can be the same asused in the step 2.

[0140] (Step 4)

[0141] The sulfone derivative represented by the general formula [7] canalso be produced by reacting the sulfide derivative represented by thegeneral formula [5] with an oxidizing agent of an appropriate amount inan appropriate solvent in the presence or absence of a catalyst, withoutisolating the sulfoxide derivative represented by the general formula[6].

[0142] The reaction temperature is any temperature ranging from 0° C. tothe reflux temperature in reaction system, preferably a temperaturerange of 0° C. to 60° C. The reaction time is 1 to 72 hours although itdiffers depending upon the compounds used.

[0143] With respect to the amounts of the reagents used in the reaction,the amount of the oxidizing agent is 1 to 3 equivalents relative to 1equivalent of the compound represented by the general formula [5] and,when the catalyst is used, the amount of the catalyst is 0.01 to 0.5equivalent.

[0144] The solvent, oxidizing agent and catalyst used can be the same asused in the step 2.

[0145] (Step 5)

[0146] The sulfide derivative represented by the general formula [5] canalso be produced by reacting a compound represented by the generalformula [8] with a mercaptan derivative represented by the generalformula [9] in a solvent or in the absence of a solvent (preferably inan appropriate solvent) in the presence of a base.

[0147] The reaction temperature is any temperature ranging from 0° C. tothe reflux temperature in reaction system, preferably a temperaturerange of 0° C. to 100° C. The reaction time is 0.5 to 24 hours althoughit differs depending upon the compounds used.

[0148] With respect to the amounts of the reagents used in the reaction,the amount of the compound represented by the general formula [9] is 1to 3 equivalents relative to 1 equivalent of the compound represented bythe general formula [8] and the amount of the base is 0.5 to 3equivalents.

[0149] As the solvent used, there can be mentioned, for example, etherssuch as diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran (THF)and the like; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone and the like;sulfur compounds such as dimethyl sulfoxide, (DMSO), sulfolane and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; alcohols such as methanol, ethanol, propanol, isopropanol,butanol, tert-butanol and the like; ketones such as acetone, 2-butanoneand the like; nitriles such as acetonitrile and the like; water; andmixtures thereof.

[0150] As the base used, there can be mentioned, for example, metalhydrides such as sodium hydride and the like; alkali metal amides suchas sodium amide, lithium diisopropylamide and the like; organic basessuch as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene andthe like; alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and the like; alkaline earth metal hydroxides such as calciumhydroxide, magnesium hydroxide and the like; alkali metal carbonatessuch as sodium carbonate, potassium carbonate and the like; alkali metalbicarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like (inorganic bases) ; and metal alkoxides such assodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

[0151] Of the compounds represented by general formula [8], thosewherein L is a halogen atom, i.e. a compound represented by the generalformula [12] and a compound represented by the general formula [13] canbe produced by the following method.

[0152] (Step 6)

[0153] wherein X¹, R¹, R², R³ and R⁴ have the same meanings as givenabove.

[0154] The isoxazoline compounds represented by the general formulas[12] and [13] can be produced by reacting an olefin derivativerepresented by the general formula [10] with an oxime derivativerepresented by the general formula [11] in a solvent or in the absenceof a solvent (preferably in an appropriate solvent) in the presence of abase. As necessary, the compounds of the general formula [12] and [13]are separated from each other and purified. However, when both R³ and R⁴are a hydrogen atom, the isoxazoline compound represented by the generalformula [12] is obtained predominantly.

[0155] The reaction temperature is any temperature ranging from 0° C. tothe reflux temperature in reaction system, preferably a temperaturerange of 0° C. to 80° C. The reaction time is 0.5 hour to 2 weeksalthough it differs depending upon the compounds used.

[0156] With respect to the amounts of the reagents used in the reaction,the amount of the compound represented by the general formula [10] is 1to 3 equivalents relative to 1 equivalent of the compound represented bythe general formula [11].

[0157] As the solvent used, there can be mentioned, for example, etherssuch as ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethyl ether, dioxane, tetrahydrofuran and the like; halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like, esters such as ethyl acetate,butyl acetate and the like; water; and mixtures thereof.

[0158] As the base used, there can be mentioned, for example, alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide and thelike; alkaline earth metal hydroxides such as calcium hydroxide,magnesium hydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metal bicarbonatessuch as sodium hydrogen carbonate, potassium hydrogen carbonate and thelike; alkali metal acetates such as sodium acetate, potassium acetateand the like; alkali metal fluorides such as sodium fluoride, potassiumfluoride and the like; and organic bases such as pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0159] Incidentally, the compound represented by the general formula[10] used in the above production process as an intermediate may be acommercial product or can be produced by a known reaction such as theWitting reaction or the like. The compound represented by the generalformula [11] can be produced by, for example, the method described inLiebigs Annalen der Chemie, 985 (1989).

[0160] The compound represented by the general formula [1] can beproduced from the previously shown compound represented by the generalformula [12] by the following methods.

[0161] (Step 7 to Step 10)

[0162] wherein X¹, R¹, R², R³, R⁴ and R⁷ have the same meanings as givenabove.

[0163] A compound represented by the general formula [15] can beproduced based on the method shown in the step 5 (step 7); a compoundrepresented by the general formula [16] can be produced based on themethod shown in the step 2 (step 8) ; the compound represented by thegeneral formula [1] can be produced from the compound of the generalformula [15] based on the method shown in the step 4 (step 10) , or fromthe compound of the general formula [16] based on the method shown inthe step 3 (step 9). The solvent, base, oxidizing agent and catalystused can be the same as used in the step 2, the step 3, the step 4 orthe step 5.

[0164] Of the compounds represented by the general formula [4], acompound represented by the general formula [21] can be produced by themethods shown below.

[0165] (Steps 11 and 12)

[0166] wherein R⁵ , X¹ and Y have the same meanings as given above; andR⁸ is an alkyl group.

[0167] (Step 11)

[0168] A compound represented by the general formula [20] can beproduced by reacting a compound of the general formula [17], [18] or[19] with a reducing agent in a solvent.

[0169] This reaction is conducted ordinarily at a temperature of −60 to150° C. for 10 minutes to 24 hours.

[0170] With respect to the amounts of the reagents used, the amount ofthe reducing agent is desired to be 0.5 to 2 equivalents per 1equivalent of the compound of the general formula [17], [18] or [19],but it can be varied appropriately depending upon the conditions of thereaction.

[0171] As the reducing agent, there can be mentioned, in production ofthe compound of the general formula [20] from the compound of thegeneral formula [17], metal hydrides such as diisobutyl aluminum hydrideand the like; metal-hydrogen complex compounds such as sodiumborohydride, lithium aluminum hydride and the like; and so forth. Inproduction of the compound of the general formula [20] from the compoundof the general formula [18] or [19], there can be mentioned, forexample, metal hydrides such as diisobutyl aluminum hydride and thelike; metal-hydrogen complex compounds such as sodium borohydride,lithium aluminum hydride and the like; and diborane.

[0172] As the solvent used, there can be mentioned, for example, etherssuch as diethyl ether, tetrahydrofuran, dioxane and the like; aromatichydrocarbons such as benzene, toluene and the like; and alcohols such asmethanol, ethanol and the like.

[0173] (Step 12)

[0174] A compound represented by the general formula [21] can beproduced by reacting the compound of the general formula [20] with ahalogenating agent in a solvent.

[0175] This reaction is conducted ordinarily at −50 to 100° C. for 10minutes to 24 hours.

[0176] With respect to the amounts of the reagents used, the amount ofthe halogenating agent is desired to be 1 to 3 equivalents per 1equivalent of the compound of the general formula [20] but it can bevaried appropriately depending upon the conditions of the reaction.

[0177] As the halogenating agent used, there can be mentioned, forexample, hydrogen chloride, hydrogen bromide, phosphorus trichloride,phosphorus tribromide, and thionyl chloride.

[0178] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloroethane, carbon tetrachlorideand the like; acids such as acetic acid and the like; and ethers such astetrahydrofuran and the like.

[0179] The compound represented by the general formula [4] can beproduced by the following method.

[0180] wherein R⁵, R⁶, X¹ and Y have the same meanings as given above.

[0181] (Step 13)

[0182] The compound represented by the general formula [4] can beproduced by reacting a compound represented by the general formula [22]with a halogenating agent in a solvent in the presence or absence of acatalyst. In this step, the reaction may be conducted under lightirradiation.

[0183] This reaction is conducted ordinarily at 30 to 150° C. for 10minutes to 24 hours.

[0184] With respect to the amounts of the reagents used, the amount ofthe halogenating agent is desired to be 1 to 10 equivalents per 1equivalent of the compound of the general formula [22] but it can bevaried appropriately depending upon the conditions of the reaction. Theamount of the catalyst is 0.01 to 0.5 equivalent.

[0185] As the halogenating agent used, there can be mentioned, forexample, halogens such as bromine, chlorine and the like;N-halosuccinimides such as N-bromosuccinimide and the like; and pyridinesalts such as pyridinium perbromide and the like.

[0186] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; and carboxylic acids suchas formic acid, acetic acid and the like.

[0187] As the catalyst used, there can be mentioned, for example,benzoyl peroxide, α, α-azobisisobutyronitrile, and mixtures thereof.

[0188] Of the compounds represented by the general formula [4], acompound represented by the general formula [24] can be produced by thefollowing method.

[0189] wherein X¹ and Y have the same meanings as given above.

[0190] (Step 14)

[0191] The compound represented by the general formula [24] can beproduced by reacting a compound represented by the general formula [23]with a hydrogen halide and formaldehyde or paraformaldehyde in a solventin the presence or absence of a Lewis acid, based on the methoddescribed in Org. Synth., III, 557 (1955) or J. Am. Chem. Soc., 72, 2216(1950), or by reacting the compound represented by the general formula[23] with a halogenomethyl ether in a solvent in the presence of a Lewisacid, based on the method described in J. Am. Chem. Soc., 97, 6155(1975).

[0192] This reaction is conducted ordinarily at −40 to 150° C. for 10minutes to 24 hours.

[0193] With respect to the amounts of the reagents used, it is desiredthat the amount of the hydrogen halide is 1 to 2 equivalents, the amountof formaldehyde or paraformaldehyde is 1 to 2 equivalents, the amount ofthe Lewis acid is 1 to 2 equivalents, and the amount of thehalogenomethyl ether is 1 to 2 equivalents, all relative to 1 equivalentof the compound of the general formula [23]. However, these amounts canbe varied appropriately depending upon the conditions of the reaction.

[0194] As the Lewis acid used, there can be mentioned, for example,titanium tetrachloride, zinc chloride, aluminum chloride and zincbromide.

[0195] As the hydrogen halide used, there can be mentioned hydrogenchloride, hydrogen bromide and hydrogen iodide.

[0196] As the solvent used, there can be mentioned, for example,halogenating hydrocarbons such as dichloroethane, carbon tetrachloride,chloroform and the like; aliphatic hydrocarbons such as hexane, heptaneand the like; ethers such as dioxane, tetrahydrofuran and the like;carboxylic acids such as acetic acid and the like; carbon disulfide; andmixtures thereof.

[0197] Of the compounds represented by the general formula [19], acompound represented by the general formula [25] can be produced by thefollowing method.

[0198] wherein Y has the same meaning as given above.

[0199] (Step 15)

[0200] The compound represented by the general formula [25] can beproduced by reacting the compound of the general formula [23] withN,N-dimethylformamide (DMF) in a solvent or in the absence of a solventin the presence of phosphoryl chloride, phosgene or thionyl chloride,based on the method described in Org. Synth., IV, 831 (1963) [Vilsmeiermethod], or by reacting the compound of the general formula [23] with adihalogenomethyl ether in a solvent in the presence of a Lewis acid,followed by hydrolysis, based on the method described in Chem. Ber., 93,88 (1960).

[0201] This reaction is conducted ordinarily at −40 to 150° C. for 10minutes to 24 hours.

[0202] With respect to the amounts of reagents used in the reaction, itis desired that the amount of phosphoryl chloride, phosgene or thionylchloride is 1 to 2 equivalents, the amount of N,N-dimethylformamide is 1to 2 equivalents, the amount of Lewis acid is 1 to 2 equivalents, andthe amount of dihalogenomethyl ether is 1 to 2 equivalents, all relativeto 1 equivalent of the compound of the general formula [23]; however,these amounts can be varied appropriately depending upon the conditionsof the reaction.

[0203] As the Lewis acid used, there can be mentioned, for example,titanium tetrachloride, tin tetrachloride, zinc chloride, aluminumchloride and zinc bromide.

[0204] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloroethane, carbon tetrachloride,chloroform and the like; aliphatic hydrocarbons such as hexane, heptaneand the like; ethers such as dioxane, tetrahydrofuran and the like;carboxylic acids such as acetic acid and the like; amides such asN,N-dimethylformamide and the like; sulfur compound such as carbondisulfide and the like; and mixtures thereof.

[0205] The compound represented by the general formula [17], [18] or[19] can be produced by the following method.

[0206] wherein X² is a chlorine atom, a bromine atom or an iodine atom;and R⁵, R⁶ and Y have the same meanings as given above.

[0207] (Steps 16 and 17)

[0208] The compound represented by the general formula [17], [18] or[19] can be produced by reacting a compound represented by the generalformula [26] with a magnesium reagent in a solvent or in the absence ofa solvent based on the method described in J. Org. Chem., 65, 4618(2000), to obtain a compound of the general formula [27] and reactingthe compound of the general formula [27] with an electrophilic reagent,or by reacting the compound of the general formula [26] with a lithiumreagent based on the method described in Synth. Commum., 24(2), 253(1994) to obtain a compound of the general formula [28] and reacting thecompound of the general formula [28] with an electrophilic reagent.

[0209] This reaction is conducted ordinarily at −100 to 150° C. for 10minutes to 24 hours.

[0210] With respect to the amounts of the reagents used in the reaction,it is desired that the amount of the magnesium reagent is 1 to 5equivalents, the amount of the electrophilic reagent is 1 to 5equivalents, or the amount of the lithium reagent is 1 to 5 equivalentsand the amount of the electrophilic reagent is 1 to 5 equivalents, allrelative to 1 equivalent of the compound of the general formula [26];however, these amounts can be varied appropriately depending upon theconditions of the reaction.

[0211] As the magnesium reagent used, there can be mentioned, forexample, metallic magnesium, isopropyl magnesium bromide and diisopropylmagnesium and the like.

[0212] As the lithium reagent used, there can be mentioned, for example,n-butyl lithium and n-hexyl lithium and the like.

[0213] As the electrophilic reagent used, there can be mentioned, forexample, esters such as ethyl formate, ethyl cyanoformate, ethyl acetateand the like; acid halides such as acetyl chloride, methyl chloroformateand the like; amides such as N,N-dimethylformamide and the like; andcarbon dioxide.

[0214] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloroethane, carbon tetrachloride,chloroform and the like; aliphatic hydrocarbons such as hexane, pentaneand the like; ethers such as dioxane, tetrahydrofuran and the like; andmixtures thereof.

[0215] A compound represented by the general formula [31] can beproduced by the following method.

[0216] wherein Y has the same meaning as given above; R⁹ is a hydrogenatom, an alkyl group, an acyl group or an alkoxycarbonyl group; R¹⁰ isan alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkylgroup, an alkoxycarbonylalkyl group, an optionally substituted benzylgroup, an optionally substituted heterocyclic alkyl group, alkenylgroup, an alkynyl group, an alkylsulfonyl group, a haloalkylsulfonylgroup, an optionally substituted aromatic heterocyclic group, anoptionally substituted phenylsulfonyl group, an acyl group, ahaloalkylcarbonyl group, an optionally substituted benzylcarbonyl groupor an optionally substituted benzoyl group; and L¹ is an eliminatablegroup such as halogen atom, C1 to C4 alkylsulfonyloxy group, C1 to C4alkylsulfonyl group, optionally substituted benzylsulfonyl group,optionally substituted phenylsulfonyloxy group, optionally substitutedbenzylsulfonyloxy group or the like; when R¹⁰ is a haloalkyl group, L¹is an eliminatable group having a reactivity higher than that of thehalogen atom which remains after haloalkylation and, when R¹⁰ is, forexample, a CHF₂ group, L¹ is a chlorine atom or a bromine atom and, whenR¹⁰ is a CH₂CF₃ group, L¹ is a chlorine atom, a bromine atom, an iodineatom, a p-toluenesulfonyloxy group, a methylsulfonyloxy group, atrifluoromethylsulfonyloxy group or the like.

[0217] (Step 18)

[0218] The compound represented by the general formula [31] can beproduced by reacting a compound represented by the general formula [29]with a compound represented by the general formula [30] in a solvent inthe presence of a base.

[0219] This reaction is conducted ordinarily at 0 to 120° C. for 10minutes to 24 hours.

[0220] With respect to the amounts of the reagents used in the reaction,the amount of the compound represented by the general formula [30] is 1to 20 equivalents and the amount of the base is 1 to 3 equivalents, allrelative to 1 equivalent of the compound represented by the generalformula [29].

[0221] As the base used, there can be mentioned, for example, alkalimetal carbonates such as sodium carbonate, potassium carbonate and thelike; alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and the like; alkali metal hydrides such as potassium hydride,sodium hydride and the like; alkali metal alkoxides such as sodiumethoxide, sodium methoxide and the like; and organic bases such as1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0222] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as chloroform, dichloroethane and thelike; ethers such as diethyl ether, tetrahydrofuran and the like;aromatic hydrocarbons such as benzene, toluene and the like; aliphatichydrocarbons such as hexane, heptane and the like; ketones such asacetone, methyl isobutyl ketone and the like; esters such as ethylacetate and the like; amides such as N-methylpyrrolidone,N,N-dimethylformamide and the like; sulfur compounds such as dimethylsulfoxide, sulfolane and the like; acetonitrile; and mixtures thereof.

[0223] A compound represented by the general formula [34] can beproduced by the following method.

[0224] wherein L¹, α, β and γ have the same meanings as given above; andR¹¹ is an alkyl group, an alkyl group mono-substituted with a groupselected from the substituent group β, a haloalkyl group, a cycloalkylgroup, an alkenyl group, an alkynyl group, an alkylsulfinyl group, analkylsulfonyl group, an alkylsulfonyl group mono-substituted with agroup selected from the substituent group γ, a haloalkylsulfonyl group,an optionally substituted phenyl group, an optionally substitutedaromatic heterocyclic group, an optionally substituted phenylsulfonylgroup, an optionally substituted aromatic heterosulfonyl group, an acylgroup, a haloalkylcarbonyl group, an optionally substitutedbenzylcarbonyl group, an optionally substituted benzoyl group, analkoxycarbonyl group, an optionally substituted benzyloxycarbonyl group,an optionally substituted phenoxycarbonyl group or a carbamoyl group(its nitrogen atom may be substituted with same or different alkylgroups or an optionally substituted phenyl group; and the carbon atomsof the pyrazole ring may be substituted with 1 to 2 same or differentgroups selected from the substituent group α.

[0225] (Step 19)

[0226] The compound represented by the general formula [34] can beproduced by reacting a compound represented by the general formula [32]with a compound represented by the general formula [33] in a solvent inthe presence of a base.

[0227] This reaction is conducted ordinarily at 0 to 120° C. for 10minutes to 24 hours.

[0228] With respect to the amounts of the reagents used in the reaction,the amount of the compound [33] is 1 to 20 equivalents and the amount ofthe base is 1 to 3 equivalents, all relative to 1 equivalent of thecompound represented by the general formula [32].

[0229] As the base and solvent used, there can be mentioned, forexample, the same substances as used in the step 18.

[0230] As the method for introducing a trifluoromethyl group into Y,there can be mentioned, for example, the methods described in J. Chem.Soc. Perkin Trans. 1, 8, 2293-2299 (1990) , J. Fluorine Chem. , 50(3) ,411-426 (1990) , J. Chem. Soc. Chem. Commun., 18, 1389-1391 (1993), J.Chem. Soc. Chem. Commun., 1, 53-54 (1992), Chem. Lett., 1719-1720(1981), Chem. Pharm. Bull., 38(9), 2446-2458 (1990), J. Chem. Soc.Perkin. Trans. 1, 921-926 (1988), Hetercycles, 37(2), 775-782 (1994),Tetrahedron Lett., 30(16), 2133-2136 (1989), J. Chem. Soc. Perkin Trans.1, 2755-2761 (1980), Hetercycles, 22(1), 117-124 (1984), Eur. J. Med.Chem. Chim. Ther., 24, 249-258 (1989) , Acta Chem. Scand. Ser. B, 38(6), 505-508 (1984) , J. Fluorine Chem., 21, 495-514 (1982), J. Chem. Soc.Chem. Commun., 10, 638-639 (1988), J. Fluorine Chem., 67(1), 5-6 (1994),J. Heterocycl. Chem., 31(6), 1413-1416 (1994), Chem. Heterocycl. Compd.,30(5), 576-578 (1994), F. Fluorine Chem., 78(2) , 177-182 (1996) , J.Heterocycl. Chem. , 34(2) 551-556 (1997), Tetrahedron, 55(52),15067-15070 (1999), and Synthesis, 11, 932-933 (1980); and methodssimilar thereto.

[0231] The compounds represented by the general formulas [4], [17],[18], [19], [20], [21], [22], [23], [24], [25], [26], [29] and [31] canbe produced by the methods described, when Y is a pyrrolyl group, inMethoden der Organischen Chemie, E6a, 556-798 (1994); when Y is apyrazolyl group, in Methoden der Organischen Chemie, E8b, 399-763 (1994)or JP-A-2000-219679; when Y is an isothiazolyl group, in Methoden derOrganischen Chemie, E8a, 668-798 (1993); when Y is an oxazolyl group, inMethoden der Organischen Chemie, E8a, 891-1019 (1993); when Y is animidazolyl group, in Methoden der Organischen Chemie, E8c, 1-215 (1994);when Y is a pyridazinyl group, in Methoden der Organischen Chemie, E9a,557-682 (1997); when Y is a pyrimidinyl group, in Methoden derOrganischen Chemie, E9b/1, 1-249 (1998); when Y is a pyrazinyl group, inMethoden der Organischen Chemie, E9b/1, 250-372 (1998); when Y is atriazinyl group, in Methoden der Organischen Chemie, E9c, 530-796(1998); when Y is a triazolyl group, in Methoden der Organischen Chemie,E8d, 305-405, 479-598 (1994); when Y is an oxadiazolyl group, inMethoden der Organischen Chemie, E8c, 397-818 (1994); when Y is abenzothienyl group, in Methoden der Organischen Chemie, E6b1, 217-322(1994); when Y is an indolyl group, in Methoden der Organischen Chemie,E6b1, 546-848 (1994) , Methoden der Organischen Chemie, E6b2, 849-1336(1994), or Unexamined International Patent Publication No. WO 97/42188;when Y is a benzoxazolyl group, in Methoden der Organischen Chemie, E8a,1020-1194 (1993); when Y is a benzoimidazolyl group, in Methoden derOrganischen Chemie, E8c, 216-391 (1994); when Y is a benzoisoxazolylgroup, in Methoden der Organischen Chemie, E8a, 226-348 (1993); when Yis a benzoisothiazolyl group, in Methoden der Organischen Chemie, E8a,799-852 (1993); when Y is an indazolyl group, in Methoden derOrganischen Chemie, E8b, 764-864 (1994); when Y is a quinolyl group, inMethoden der Organischen Chemie, E7a, 290-570 (1991); when Y is anisoquinolyl group, in Methoden der Organischen Chemie, E7a, 571-758(1991); when Y is a phthalazinyl group, in Methoden der OrganischenChemie, E9a, 744-789 (1997); when Y is a quinoxalinyl group, in Methodender Organischen Chemie, E9b/2, 93-265 (1998); when Y is a quinazolinylgroup, in Methoden der Organischen Chemie, E9b/2, 1-192 (1998); when Yis a cinnolinyl group, in Methoden der Organischen Chemie, E9a, 683-743(1997); and when Y is a benzotriazolyl group, in Methoden derOrganischen Chemie, E8d, 406-478 (1994); or by methods similar thereto.

PRODUCTION PROCESS 2

[0232]

[0233] wherein R¹, R², R³, R⁴, R⁵, R⁶ and α have the same meanings asgiven above; and the carbon atoms of the pyrazole ring may besubstituted with 1 to 2 same or different groups selected from thesubstituent group α.

[0234] (Step 20)

[0235] A compound of the present invention represented by the generalformula [36] can be produced by reacting a compound of the presentinvention represented by the general formula [35] (which can be producedby the production process 1) with an acid in a solvent.

[0236] This reaction is conducted ordinarily at 0 to 120° C. for 10minutes to 24 hours.

[0237] With respect to the amounts of the reagents used in the reaction,the amount of the acid is desired to be 1 to 10 equivalents per 1equivalent of the present compound represented by the general formula[35], but can be varied appropriately depending upon the conditions ofthe reaction.

[0238] As the acid used, there can be mentioned, for example,hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

[0239] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethylsulfoxide (DMSO), sulfolane and the like; carboxylic acids such asformic acid, acetic acid and the like; and water.

PRODUCTION PROCESS 3

[0240]

[0241] wherein R¹, R², R³, R⁴, R⁵, R⁶, R¹¹ and α have the same meaningsas given above; and the carbon atoms of the pyrazole ring may besubstituted with 1 to 2 same or different groups selected from thesubstituent group α.

[0242] (Step 21)

[0243] A compound of the present invention represented by the generalformula [38] can be produced by reacting a compound of the presentinvention represented by the general formula [36] (which can be producedby the production process 2) with the compound represented by thegeneral formula [33] in a solvent in the presence of a base.

[0244] With respect to the amounts of the reagents used in the reaction,the amount of the compound represented by the general formula [33] is 1to 3 equivalents and the amount of the base is 1 to 3 equivalents, allrelative to 1 equivalent of the compound represented by the generalformula [36].

[0245] As the solvent used, there can be mentioned, for example, etherssuch as dioxane, tetrahydrofuran (THF) and the like; halogenatedhydrocarbons such as dichloroethane, carbon tetrachloride,chlorobenzene, dichlorobenzene and the like; amides such asN,N-dimethylacetamide, N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidinone and the like; sulfur compounds such as dimethylsulfoxide (DMSO), sulfolane and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; alcohols such as methanol,ethanol, propanol, isopropanol, butanol, tert-butanol and the like;ketones such as acetone, 2-butanone and the like; nitriles such asacetonitrile and the like; water; and mixtures thereof.

[0246] As the base used, there can be mentioned, for example, metalhydrides such as sodium hydride and the like; alkali metal amides suchas sodium amide, lithium diisopropylamide and the like; organic basessuch as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene andthe like; alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide and the like; alkaline earth metal hydroxides such as calciumhydroxide, magnesium hydroxide and the like; alkali metal carbonatessuch as sodium carbonate, potassium carbonate and the like; alkali metalbicarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like; and metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide and the like.

PRODUCTION PROCESS 4

[0247]

[0248] wherein R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ have the same meanings asgiven above; R¹² is a trifluoromethyl group, a difluoromethyl group or adifluoromethoxy group; X³ is a chlorine atom or a fluorine atom; R¹³ isan alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkylgroup, an alkenyl group, an alkynyl group, an optionally substitutedphenyl group, an optionally substituted aromatic heterocyclic group, analkoxycarbonylalkyl group, an optionally substituted heteroalkyl groupor an optionally substituted benzyl group; R¹⁴ is an alkyl group, ahaloalkyl group, an optionally substituted phenyl group, an optionallysubstituted aromatic heterocyclic group, an alkoxycarbonylalkyl group oran optionally substituted benzyl group; R¹⁵ and R¹⁶ may be the same ordifferent and are each a hydrogen atom, an alkyl group, an optionallysubstituted phenyl group, an acyl group, a haloalkylcarbonyl group, anoptionally substituted benzylcarbonyl group, an optionally substitutedbenzoyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, anoptionally substituted benzylsulfonyl group or an optionally substitutedphenylsulfonyl group; and Z¹ is a sulfur atom or N-R¹⁷ (R¹⁷ is ahydrogen atom or R¹⁰).

[0249] A compound of the present invention represented by the generalformula [41], the general formula [43] or the general formula [45] canbe produced by reacting a compound of the present invention representedby the general formula [39] with a compound represented by the generalformula [40] (step 22) , the general formula [42] (step 23) or thegeneral formula [44] (step 24) in the absence or presence of a solventand, as necessary, in the presence of a base.

[0250] This reaction is conducted ordinarily at 20 to 200° C.,preferably at 30 to 180° C. for 10 minutes to 48 hours, under pressureif necessary.

[0251] With respect to the amounts of the reagents used in the reaction,the amount of the compound represented by the general formula [40], thegeneral formula [42] or the general formula [44] is 1 to 20 equivalentsper 1 equivalent of the compound of the present invention represented bythe general formula [39].

[0252] As the base used, there can be mentioned, for example, inorganicbases such as potassium carbonate, sodium hydroxide, potassium hydride,sodium hydride and the like; alkali metal alkoxides such as sodiumethoxide, sodium methoxide and the like; and organic bases such as1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0253] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as chloroform and the like; ethers such asdiethyl ether, tetrahydrofuran and the like; aromatic hydrocarbons suchas benzene, toluene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ketones such as acetone, methyl isobutyl ketoneand the like; esters such as ethyl acetate and the like; amides such asN-methylpyrrolidone, N,N-dimethylformamide and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; nitrilessuch as acetonitrile and the like; and mixtures thereof.

PRODUCTION PROCESS 5

[0254]

[0255] wherein R¹, R², R³ R⁴, R⁵, R⁶, R¹², R¹³ and Z¹ have the samemeanings as given above.

[0256] (Step 25) A compound of the present invention represented by thegeneral formula [47] can be produced by reacting the present inventioncompound represented by the general formula [41] with an acid in asolvent.

[0257] This reaction is conducted ordinarily at 0 to 120° C. for 10minutes to 24 hours.

[0258] With respect to the amounts of the reagents used in the reaction,the amount of the acid is desirably 1 to 10 equivalents per 1 equivalentof the present invention compound represented by the general formula[41] but can be varied appropriately depending upon the conditions ofthe reaction.

[0259] As the acid and solvent used, there can be mentioned the samesubstances as used in the production process 2.

PRODUCTION PROCESS 6

[0260]

[0261] wherein Y, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, L¹ and α have the samemeanings as given above; and Y may be substituted with 1 to 5 same ordifferent groups selected from the substituent group α.

[0262] (Step 26)

[0263] A compound of the present invention represented by the generalformula [49] can be produced by reacting a compound of the presentinvention represented by the general formula [48] with the compoundrepresented by the general formula [30] in a solvent in the presence ofa base.

[0264] This reaction is conducted ordinarily at 0 to 150° C. for 10minutes to 24 hours.

[0265] With respect to the amounts of the reagents used in the reaction,the amount of the base is desirably 1 to 1.2 equivalents per 1equivalent of the present invention compound represented by the generalformula [48] but can be varied appropriately depending upon theconditions of the reaction.

[0266] As the base and solvent used, there can be mentioned the samesubstances as used in the production process 3.

PRODUCTION PROCESS 7

[0267]

[0268] wherein Y, R¹, R², R³, R⁴, R⁵, R⁶ and α have the same meanings asgiven above; R¹⁸ is an alkyl group, an optionally substituted benzylgroup or an optionally substituted phenyl group; and Y may besubstituted with 1 to 5 same or different groups selected from thesubstituent group α.

[0269] (Step 27)

[0270] A compound of the present invention represented by the generalformula [51] can be produced by hydrolyzing a compound of the presentinvention represented by the general formula [50] in water or awater/solvent mixture in the presence or absence of a base.

[0271] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0272] With respect to the amounts of the reagents used in the reaction,the amount of the base, when used, is desirably 1 to 2 equivalents per 1equivalent of the present invention compound represented by the generalformula [50] but can be varied appropriately depending upon theconditions of the reaction.

[0273] As the base used, there can be mentioned, for example, inorganicbases such as potassium carbonate, sodium hydride, sodium hydroxide andthe like; and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undeceneand the like.

[0274] As the solvent to be mixed with water, there can be mentioned,for example, alcohols such as methanol, ethanol and the like; etherssuch as tetrahydrofuran and the like; ketones such as acetone, methylisobutyl ketone and the like; amides such as N,N-dimethylformamide andthe like; sulfur compounds such as dimethyl sulfoxide, sulfolane and thelike; nitriles such as acetonitrile and the like; and mixtures thereof.

PRODUCTION PROCESS 8

[0275]

[0276] wherein Y, R¹, R², R³, R⁴, R⁵, R⁶ and α have the same meanings asgiven above; R¹⁹ is a hydrogen atom or an alkyl group; R²⁰ is an alkylgroup; and Y may be substituted with 1 to 5 same or different groupsselected from the substituent group α.

[0277] (Step 28)

[0278] A compound of the present invention represented by the generalformula [54] can be produced by reacting a compound of the presentinvention represented by the general formula [52] with a compoundrepresented by the general formula [53] in a solvent in the presence ofa base.

[0279] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0280] With respect to the amounts of the reagents used in the reaction,it is desired that the amount of the compound represented by the generalformula [53] is 1 to 5 equivalents and the amount of the base is 1 to 10equivalents, all relative to 1 equivalent of the compound of the presentinvention represented by the general formula [52], but these amounts maybe varied appropriately depending upon the conditions of the reaction.

[0281] As the base used, there can be mentioned, for example, metalcarbonates such as potassium carbonate, sodium carbonate and the like;metal acetates such as potassium acetate, sodium acetate and the like;and organic bases such as triethylamine, dimethylamine,1,8-diazabicyclo[5.4.0]-7-undecene and the like.

[0282] As the salt of NH₂OR²⁰ used, there can be mentioned NH₂OR²⁰hydrochloride, NH₂OR²⁰ sulfate, etc.

[0283] As the solvent used, there can be mentioned, for example,alcohols such as methanol, ethanol and the like; ethers such astetrahydrofuran and the like; amides such as N,N-dimethylformamide andthe like; water; and mixtures thereof.

PRODUCTION PROCESS 9

[0284]

[0285] wherein Y, R¹, R², R³, R⁴, R⁵, R⁶ and α have the same meanings asgiven above; R²¹ and R²² are each a hydrogen atom or an alkyl group; andY may be substituted with 1 to 5 same or different groups selected fromthe substituent group α.

[0286] (Steps 29 and 30)

[0287] A compound of the present invention represented by the generalformula [58] can be produced by reacting the present invention compoundrepresented by the general formula [51] with a halogenating agent in thepresence or absence of a solvent to produce a compound of the presentinvention represented by the general formula [56] (step 29) and thenreacting the compound represented by the general formula [56] with acompound represented by the general formula [57] in the presence orabsence of a solvent (step 30).

[0288] The reaction of the step 29 is conducted ordinarily at 0 to 100°C. for 10 minutes to 24 hours.

[0289] With respect to the amounts of the regents used in the reaction,the amount of the halogenating agent is desired to be 1 to 100equivalents per 1 equivalent of the present invention compoundrepresented by the general formula [51], but may be varied appropriatelydepending upon the conditions of the reaction.

[0290] As the halogenating agent used, there can be mentioned, forexample, thionyl chloride, oxalyl chloride, etc.

[0291] As the solvent used, there can be mentioned, for example,halogenated hydrocarbons such as dichloromethane, chloroform and thelike; ethers such as diethyl ether, tetrahydrofuran and the like; andaromatic hydrocarbons such as benzene, toluene and the like.

[0292] The reaction of the step 30 is conducted ordinarily at 0 to 100°C. for 10 minutes to 24 hours.

[0293] With respect to the amounts of the regents used in the reaction,the amount of the compound represented by the general formula [57] isdesired to be 2 to 100 equivalents per 1 equivalent of the presentinvention compound represented by the general formula [56], but may bevaried appropriately depending upon the conditions of the reaction.

[0294] As the solvent used, there can be mentioned, for example, thesame solvents as used in the step 29.

PRODUCTION PROCESS 10

[0295]

[0296] wherein Z¹, R¹, R², R³, R⁴, R⁵, R⁶, R¹² and X³ have the samemeanings as given above.

[0297] A compound of the present invention represented by the generalformula [60] can be produced by reacting the present invention compoundrepresented by the general formula [39] with a compound represented bythe general formula [59] in a solvent.

[0298] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0299] With respect to the amounts of the regents used in the reaction,the amount of the compound represented by the general formula [59] isdesired to be 1 to 2 equivalents per 1 equivalent of the presentinvention compound represented by the general formula [39], but may bevaried appropriately depending upon the conditions of the reaction.

[0300] As the solvent used, there can be mentioned, for example, etherssuch as dioxane, tetrahydrofuran and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; ketonessuch as acetone, 2-butanone and the like; nitriles such as acetonitrileand the like; water; and mixtures thereof.

PRODUCTION PROCESS 11

[0301]

[0302] wherein Y, R¹, R², R³, R⁴, R⁵, R⁶ and α have the same meanings asgiven above; R²³ is an alkyl group, a haloalkyl group, a cycloalkylgroup, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, analkoxycarbonylalkyl group, an optionally substituted heteroalkyl groupor an optionally substituted benzyl group; and Y may be substituted with1 to 5 same or different groups selected from the substituent group α.

[0303] (Step 32)

[0304] A compound of the present invention represented by the generalformula [62] can be produced by a known method (Synthesis, 1981, 1-28)of reacting the present invention compound represented by the generalformula [48] with a compound represented by the general formula [61] inthe presence of an azo compound and triphenylphosphine.

[0305] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0306] With respect to the amounts of the reagents used in the reaction,it is desired that the amount of the compound represented by the generalformula [61] is 1 to 1.5 equivalents, the amount of the azo compound is1 to 1.5 equivalents and the amount of triphenylphosphine is 1 to 1.5equivalents, all relative to 1 equivalent of the present inventioncompound represented by the general formula [48], but these amounts canbe varied appropriately depending upon the conditions of the reaction.

[0307] As the solvent used, there can be mentioned, for example, etherssuch as dioxane, tetrahydrofuran and the like; halogenated hydrocarbonssuch as dichloroethane, carbon tetrachloride, chlorobenzene,dichlorobenzene and the like; amides such as N,N-dimethylacetamide,N,N-dimethylformamide, N-methyl-2-pyrrolidinone and the like; sulfurcompounds such as dimethyl sulfoxide, sulfolane and the like; aromatichydrocarbons such as benzene, toluene, xylene and the like; nitrilessuch as acetonitrile and the like; and mixtures thereof.

[0308] As the azo compound used, there can be mentioned, for example,diethyl azodicarboxylate and diisopropyl azodicarboxylate.

PRODUCTION PROCESS 12

[0309]

[0310] wherein X³, n, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰ and α have the samemeanings as given above; Z² is an oxygen atom, a sulfur atom or N-R¹⁷;R¹⁷ is a hydrogen atom or R¹⁰, m is an integer of 1 to 4; and the carbonatom at the 3-position of the pyrazole ring may be substituted with agroup selected from the substituent group α.

[0311] (Step 33)

[0312] A compound of the present invention represented by the generalformula [64] can be produced by reacting a compound of the presentinvention represented by the general formula [63] in a solvent in thepresence of a base.

[0313] This reaction is conducted ordinarily at 0 to 100° C. for 10minutes to 24 hours.

[0314] With respect to the amounts of the reagents used in the reaction,the amount of the base is desirably 1 to 3 equivalents per 1 equivalentof the present invention compound represented by the general formula[63], but may be varied appropriately depending upon the conditions ofthe reaction.

[0315] As the base and solvent used, there can be mentioned the samebases and solvents as used in the production process 3.

[0316] Next, the process for production of the present inventioncompound, the method for formulation of the present invention herbicide,and the application of the present herbicide are described specificallyby way of examples. Incidentally, description is also made on theprocess for production of an intermediate for the present inventioncompound.

EXAMPLE 1

[0317] Production of3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 1)

[0318] 1.2 g (15.0 mmoles) of sodium hydrosulfide hydrate (purity: 70%)was added into a solution of 2.1 g (10.0 mmoles) of5-chloromethyl-5-methyl-3-methylsulfonyl-2-isoxazoline dissolved in 20ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Then,there were added 2.1 g (15.0 mmoles) of anhydrous potassium carbonate,2.3 g (15.0 mmoles) of Rongalit and 2.8 g (10.0 mmoles) of4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-lH-pyrazole. Themixture was stirred at room temperature for 2 hours to give rise to areaction. After the completion of the reaction, the reaction mixture waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution, followed by drying over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography to obtain 3.3 g (yield: 100.0%) of3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.

EXAMPLE 2

[0319] Production of3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 2)

[0320] 4.3 g (25.0 mmoles) of m-chloroperbenzoic acid (70%) was added,with ice-cooling, into a solution of 3.3 g (10.0 mmoles) of3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise a reaction. After the completionof the reaction, the reaction mixture was poured into water andextraction with chloroform was conducted. The resulting organic layerwas washed with an aqueous sodium hydrogensulfite solution, water, anaqueous sodium hydrogencarbonate solution, water and an aqueous sodiumchloride ride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with hexane to obtain 2.8 g (yield:76.0%) of a white powder (melting point: 114 to 116° C.) of3-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline.

[0321]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.63 (2H,s), 3.96 (3H,s), 3.62(2H,q), 3.32 (2H,ABq, J=13.4, Δυ=164.1 Hz) , 1.63 (3H,s)

EXAMPLE 3

[0322] Production of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 3)

[0323] Into a solution of 24.2 g (70.9 mmoles) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methane-thioldissolved in 20 ml of N,N-dimethylformamide were added 11.8 g (85.0mmoles) of anhydrous potassium carbonate and 20 ml of aN,N-dimethylformamide solution containing 2.1 g (10.0 mmoles) of5-chloromethyl-5-methyl-3-methylsulfonyl-2-isoxazoline. The mixture wasstirred overnight to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water and extractionwith ethyl acetate was conducted. The resulting organic layer was washedwith water and then dried over anhydrous magnesium sulfate. Theresulting solution was filtered and the filtrate was subjected toreduced pressure distillation to remove the solvent contained therein.The residue was purified by silica gel column chromatography to obtain23.1 g (yield: 80.5%) of a colorless viscous liquid (n_(D) ²⁰ =1.5051)of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.

[0324]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.24 (2H,s), 3.55 (2H,q), 3.02 (2H,ABq, J=16.7, Δυ=110.5 Hz), 1.71 (9H,s), 1.57 (3H,s)

EXAMPLE 4

[0325] Production of3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 4)

[0326] Into 100 ml of an acetic acid solution of 25% hydrobromic acidwas added 22.0 g (54.4 mmoles) of3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.The mixture was stirred at room temperature for 2 hours and at 40° C.for 1 hour to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and then dried over anhydrous magnesium sulfate. The resultingsolution was filtered and the filtrate was subjected to reduced pressuredistillation to remove the solvent contained therein. The resultingcrystals were washed with hexane to obtain 17.7 g (yield: 93.7%) of amilky white powder (melting point: 105 to 107° C.) of3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.

[0327]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.26 (2H,s), 3.56 (2H,q), 3.03 (2H,ABq, J=16.7, Δυ=111.8 Hz), 1.56 (3H,s)

EXAMPLE 5

[0328] Production of3-(1-ethyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 5) and3-(1-ethyl-3-chloro-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazline(present invention compound No. 6)

[0329] 0.6 g (4.3 mmoles) of anhydrous potassium carbonate and 0.74 g(4.7 mmoles) of ethyl iodide were added into a solution of 1.5 g (4.3mmoles) of3-(5-chlorotrifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazolinedissolved in 25 ml of N,N-dimethylformamide. The mixture was stirred atroom temperature for 5 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous citric acid solutionand a saturated aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was filtered and thefiltrate was subjected to reduced pressure distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography to obtain 0.91 g (yield: 56.0%) of3-(1-ethyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazolineand 0.45 g (yield: 28.0%) of3-(1-ethyl-3-chloro-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazline.

EXAMPLE 6

[0330] Production of3-(1-ethyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 7)

[0331] 1.31 g (5.3 mmoles) of m-chloroperbenzoic acid (70%) was added,with ice-cooling, into a solution of 0.91 g (2.4 mmoles) of3-91-ethyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazolinedissolved in 40 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with diisopropyl ether to obtain 0.81 g(yield: 82.0%) of a white powder (melting point: 123 to 124° C.) of3-(1-ethyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline.

[0332]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.64 (2H,s), 4.29 (2H,q), 3.62(2H,q), 3.30 (2H, ABq, J=17.8, Δυ=125.6 Hz) , 1.55-1.50 (6H,m)

EXAMPLE 7

[0333] Production of3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 8)

[0334] 3.4 g (42.3 mmoles) of sodium hydrosulfide hydrate (purity: 70%)was added into a solution of 4.6 g (21.6 mmoles) of3-methylsulfonyl-5-chloromethyl-5-methyl-2-isoxazoline dissolved in 70ml of DMF. The mixture was stirred for 2 hours. Then, there were added3.0 g (21.6 mmoles) of potassium carbonate, 3.3 g (21.6 mmoles) ofRongalit and 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine. Themixture was stirred at room temperature for 21 hours to give rise to areaction. After the completion of the reaction, the reaction mixture waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution, followed by drying over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (solvent system: hexane-ethyl acetate) toobtain 1.9 g (yield: 30.3%) of3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.

[0335]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.78 (1H,s), 4.57 (2H,q), 4.45(2H,s), 3.57 (2H,q), 3.03 (2H, ABq, J=16.8, Δυ=114.3 Hz), 1.58 (3H,s),1.45 (3H,t)

EXAMPLE 8

[0336] Production of3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline(present invention compound No. 9)

[0337] 3.2 g (12.9 mmoles) of m-chloroperbenzoic acid (70%) was added,with ice-cooling, into a solution of 1.9 g (5.1 mmoles) of3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazolinedissolved in 30 ml of chloroform. The mixture was stirred at roomtemperature for 5 hours to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water andextraction with chloroform was conducted. The resulting organic layerwas washed with an aqueous sodium hydrogensulfite solution, an aqueoussodium hydrogencarbonate solution, and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The resulting crystals were washedwith hexane to obtain 1.8 g (yield: 87.7%) of white crystals (meltingpoint: 76.0 to 78.0° C.) of3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylsulfonyl)-5-chloromethyl-5-methyl-2-isoxazoline.

[0338]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.87 (1H,s), 5.03 (2H,s), 4.59(2H,q), 3.64 (2H,q), 3.33 (2H, ABq, J=17.7, Δυ=125.9 Hz), 1.64 (3H,s),1.46 (3H,t)

EXAMPLE 9

[0339] Production of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 10)

[0340] 6.9 g (85.8 mmoles) of sodium hydrosulfide hydrate (purity: 70%)was added, at room temperature, into a solution of 9.1 g (42.9 mmoles)of 5-chloromethyl-5-methyl-3-methylsulfonyl-2-isoxazoline dissolved in50 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours.Then, there were added 5.9 g (42.9 mmoles) of anhydrous potassiumcarbonate, 6.6 g (42.9 mmoles) of Rongalit and the crude product of4-bromomethyl-1-ethyl-5-fluoro-3-trifluoromehtyl-1H-pyrazole (equivalentto 42.9 mmoles) obtained in Reference Example 20. The mixture wasstirred at room temperature for 30 minutes to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with water and then dried overanhydrous magnesium sulfate. The resulting solution was subjected toreduced pressure distillation to remove the solvent contained therein.The residue was purified by silica gel column chromatography to obtain10.3 g (yield: 66.9%) of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyraz-ol-4-ylmethylthio)-5-methyl-2-isoxazoline.

[0341]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.15-4.08 (4H,m), 3.54 (2H,q), 3.01(2H, ABq, J=16.7, Δυ=110.8 Hz), 1.55 (3H,s), 1.47 (3H,t)

EXAMPLE 10

[0342] Production of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention compound No. 11)

[0343] 1.23 g (5.0 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of 0.72 g (2.0 mmoles) of5-chloromethyl-3-91-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with n-hexane to obtain 0.64 g (yield:82.1%) of a white powder (melting point: 73 to 75° C.) of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0344]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.56 (2H,s), 4.17 (2H,q), 3.61(2H,q), 3.31 (2H, ABq, J=17.8, Δυ=123.6 Hz) , 1.58 (3H,s) , 1.50 (3H,t)

EXAMPLE 11

[0345] Production of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 12)

[0346] 4.3 g (22.5 mmoles) of sodium methoxide (in the form of a 28%methanol solution) was added, at room temperature, into a solution of5.4 g (15.0 mmoles) of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 30 ml of methanol. The mixture was heated for refluxing for8 hours, to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography to obtain 3.3 g (yield: 59.1%) of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline.

[0347]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.26 (2H,s), 4.06 (5H,m), 3.55(2H,q), 3.02 (2H, ABq, J=16.9, Δυ=110.5 Hz) , 1.56 (3H,s) , 1.41 (3H,t)

EXAMPLE 12

[0348] Production of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention compound No. 13)

[0349] 1.24 g (5.0 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of 0.74 g (2.0 mmoles) of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with n-hexane to obtain 0.72 g (yield:89.2%) of a white powder (melting point: 139 to 140° C.) of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0350]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.60 (2H,s), 4.13-4.06 (5H,m), 3.30(2H, ABq, J=17.8, Δυ=122.8 Hz), 1.58 (3H,s), 1.46 (3H,t)

EXAMPLE 13

[0351] Production of5-chloromethyl-3-(1-ethyl-5-methylthio-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 14)

[0352] 4.21 g (9.0 mmoles) of sodium methyl thioalcoholate (in the formof a 15% aqueous solution) was added, at room temperature, into asolution of 1.08 g (3.0 mmoles) of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred atroom temperature overnight to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with ethyl acetate was conducted. The resulting organiclayer was washed with water and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein to obtain a crude product of5-chloromethyl-3-(1-ethyl-5-methylthio-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.

EXAMPLE 14

[0353] Production of5-chloromethyl-3-(1-ethyl-5-methylsulfonyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention product No. 15)

[0354] 3.74 g (15.0 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of a crude product of5-chloromethyl-3-(1-ethyl-5-methylthio-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(equivalent to 3.0 mmoles) dissolved in 30 ml of chloroform. The mixturewas stirred at room temperature for 20 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with chloroform was conducted. The resultingorganic layer was washed with an aqueous sodium hydrogensulfitesolution, water, an aqueous sodium hydrogencarbonate solution, water andan aqueous sodium chloride solution in this order and then dried overanhydrous magnesium sulfate. The resulting solution was subjected toreduced pressure distillation to remove the solvent contained therein.The resulting crystals were washed with n-hexane to obtain 1.15 g(yield: 84.8%) of a white powder (melting point: 113 to 114° C.) of5-chloromethyl-3-(1-ethyl-5-methylsulfonyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0355]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 5.08 (2H,bR), 4.60 (2H,q), 3.64(2H,q), 3.41 (3H,s), 3.36 (2H, ABq, J=17.5, Δυ=163.1 Hz), 1.65 (3H,s),1.60 (3H,t)

EXAMPLE 15

[0356] Production of5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention product No. 16)

[0357] 0.30 g (6.0 mmoles) of sodium cyanide was added, at roomtemperature, into a solution of 1.08 g (3.0 mmoles) of5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at50° C. for 10 hours to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water and extractionwith ethyl acetate was conducted. The resulting organic layer was washedwith water and an aqueous sodium chloride solution in this order andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography to obtain 1.10 g (yield: quantitative) of5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.

EXAMPLE 16

[0358] Production of5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention product No. 17)

[0359] 1.85 g (7.5 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of 1.10 g (3.0 mmoles) of5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 20 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with n-hexane to obtain 1.15 g (yield:84.8%) of a white powder (melting point: 76 to 78° C.) of5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0360]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.73 (2H,s), 4.45 (2H,q), 3.62(2H,q), 3.35 (2H, ABq, J=17.6, Δυ=129.6 Hz), 1.59-1.46 (6H,m)

EXAMPLE 17

[0361] Production of5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 18)

[0362] 10 ml of boron tribromide (2 M/liter of dichloromethane solution,20.2 mmoles) was added, at −60 ° C., into a solution of 2.5 g (6.7mmoles) of5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazolinedissolved in 30 ml of dichloromethane. The mixture was stirred at roomtemperature overnight to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into ice water andextraction with chloroform was conducted. The resulting organic layerwas washed with water and an aqueous sodium chloride solution in thisorder and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography to obtain 1.6 g (yield: 66.7%) of5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.

EXAMPLE 18

[0363] Production of5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention product No. 19)

[0364] 0.3 g (5.4 mmoles) of ethanol and 1.4 g (5.4 mmoles) oftriphenylphosphine were added, at room temperature, into a solution of1.6 g (4.5 mmoles) of5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazolinedissolved in 20 ml of tetrahydrofuran. Thereto was added, withice-cooling, 1.1 g (5.4 mmoles) of diisopropyl azodicarboxylate. Themixture was stirred for 1 hour to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with ethyl acetate was conducted. The resulting organiclayer was washed with water and an aqueous sodium chloride solution inthis order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography to obtain 1.5 g (yield: 86.8%) of5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.

EXAMPLE 19

[0365] Production of5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention product No. 20)

[0366] 2.4 g (9.7 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of 1.5 g (3.9 mmoles) of5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with diisopropyl ether to obtain 0.71 g(yield: 43.8%) of a white powder (melting point: 67 to 69° C.) of5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0367]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.58 (2H,s), 4.32 (2H,q), 4.09(2H,q), 3.61 (2H,q), 3.28 (2H, ABq, J=17.8, Δυ=121.7 Hz), 1.62 (3H,s),1.48-1.43 (6H,m)

EXAMPLE 20

[0368] Production of5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 21)

[0369] 6.4 g (80.0 mmoles) of sodium hydrosulfide hydrate (purity: 70%)was added, at room temperature, into a solution of 8.5 g (40.0 mmoles)of 5-chloromethyl-5-methyl-3-methylsulfonyl-2-isoxazoline dissolved in40 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour.Then, there were added, with ice-cooling, 6.6 g (48.0 mmoles) ofanhydrous potassium carbonate, 7.4 g (48.0 mmoles) of Rongalit and 10.4g (40.0 mmoles) of4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole. Themixture was stirred with ice-cooling for 30 minutes, to give rise to areaction. After the completion of the reaction, the reaction mixture waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with water and then dried overanhydrous magnesium sulfate. The resulting solution was subjected toreduced pressure distillation to remove the solvent contained therein.The residue was purified by silica gel column chromatography to obtain11.8 g (yield: 85.5%) of a light yellow viscous liquid (refractiveindex: n_(D) ²⁰=1.4974) of5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-iso-xazoline.

[0370]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.15 (2H,s), 3.80 (3H,s), 3.54(2H,q), 3.01 (2H, ABq, J=16.8, Δυ=147.8 Hz), 1.53 (3H,s)

EXAMPLE 21

[0371] Production of5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 22)

[0372] 0.9 g (4.4 mmoles) of sodium methoxide (in the form of a 28%methanol solution) was added, at room temperature, into a solution of1.0 g (2.9 mmoles) of5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of methanol. The mixture was heated for refluxing for5 hours, to give rise to a reaction. After the completion of thereaction, the reaction mixture was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution in this order, and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography to obtain 3.3 g (yield: quantitative) of5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmeth-ylthio)-5-methyl-2-isoxazoline.

[0373]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.26 (2H,s), 4.06 (3H,s), 3.72(3H,s), 3.55 (2H,q), 3.02 (2H, ABq, J=16.7, Δυ=111.0 Hz), 1.56 (3H,s)

EXAMPLE 22

[0374] Production of5-chloromethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 23)

[0375] 28.0 ml of boron tribromide (2 M/liter of a dichloromethanesolution, 55.9 mmoles) was added, at 0° C., into a solution of 10.0 g(28.0 mmoles) of5-chloromethyl-3-(5-methoxy-l-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazolinedissolved in 30 ml of dichloromethane. The mixture was stirred at roomtemperature for 30 minutes to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into icewater and extraction with ethyl acetate was conducted. The resultingorganic layer was washed with water and an aqueous sodium chloridesolution in this order, and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The resulting crystals were washedwith n-hexane to obtain 8.4 g (yield: 87.2%) of a light pink powder(melting point: 111 to 112° C. ) of5-chloromethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-iso-xazoline.

[0376]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.01 (2H,s), 3.69 (3H,s), 3.55(2H,q), 3.09 (2H, ABq, J=17.0, Δυ=114.4 Hz), 1.56 (3H,s)

EXAMPLE 23

[0377] Production of5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline(present invention compound No. 24)

[0378] 0.5 g (3.5 mmoles) of anhydrous potassium carbonate was added, atroom temperature, into a solution of 1.0 g (2.9 mmoles) of5-chloromethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazolinedissolved in 10 ml of N,N-dimethylformamide. Thereto was added, at roomtemperature, 0.6 g (3.5 mmoles) of isopropyl iodide. The mixture wasstirred for 30 minutes to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water andextraction with ethyl acetate was conducted. The resulting organic layerwas washed with water and an aqueous sodium chloride solution in thisorder, and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein. The residue was purified by silica gel columnchromatography to obtain 0.5 g (yield: 45.0%) of5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.

EXAMPLE 24

[0379] Production of5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline(present invention compound No. 25)

[0380] 0.65 g (2.64 mmoles) of m-chloroperbenzoic acid (purity: 70%) wasadded, with ice-cooling, into a solution of 0.5 g (1.2 mmoles) of5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxa-zolinedissolved in 10 ml of chloroform. The mixture was stirred at roomtemperature for 20 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with an aqueous sodium hydrogensulfite solution, water,an aqueous sodium hydrogencarbonate solution, water and an aqueoussodium chloride solution in this order and then dried over anhydrousmagnesium sulfate. The resulting solution was subjected to reducedpressure distillation to remove the solvent contained therein. Theresulting crystals were washed with diisopropyl ether to obtain 0.49 g(yield: 90.0%) of a light yellow viscous liquid of5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5-methyl-2-isoxazoline.

[0381]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.64 (1H,s), 4.51 (2H,s), 3.76(3H,s), 3.61 (2H,q), 3.24 (2H, ABq, J=17.8, Δυ=116.9 Hz), 1.61 (3H,s),1.40 (6H,d)

[0382] The compounds produced based on the methods of Examples 1 to 24are shown in Tables 58 to 60. TABLE 58 Melting point (° C.) or Compoundrefractive index No. Structural formula (nD20) 26

111-112 27

130-132 28

122-124 29

122-123 30

155-156 31

117-118 32

137-138 33

114-116 34

125-126 35

77-78

[0383] TABLE 59 Melting point (° C.) or Compound refractive index No.Structural formula (nD20) 36

114-115 37

125-126 38

1.4828 39

77-79 40

139-140 41

101-103 42

123-124 43

106-107 44

Impossible to measure 45

Impossible to measure

[0384] TABLE 60 Melting point (° C.) or Compound refractive index No.Structural formula (nD20) 46

Impossible to measure 47

88-90 48

80-81 49

1.5006

PRODUCTION OF INTERMEDIATES Reference Example 1

[0385] Production of 1-methyl-3-trifluoromethyl-1H-pyrazol-5-ol

[0386] 23.0 g (0.5 M) of monomethylhydrazine and 5 ml of concentratedhydrochloric acid were added into a solution of 92.1 g (0.5 M) of ethyltrifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture washeated and refluxed for 2 days to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was subjected toreduced pressure distillation to remove the most part of the solventcontained therein. The residue was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting material wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was washed with n-hexane to obtain 60.0 g(yield: 72.2%) of a white powder of1-methyl-3-trifluoromethyl-1H-pyrazol-5-ol.

Reference Example 2

[0387] Production of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-carboaldehyde

[0388] 360 g (2.31 M) of phosphorus oxychloride was added to 60.0 g(0.76 M) of N,N-dimethylformamide with ice-cooling. Thereto was added,at room temperature, 64.0 g (0.385 M) of1-methyl-3-trifluoromethyl-1H-pyrazol-5-ol. The mixture was heated andrefluxed for 1 hour to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water withice-cooling, and extraction with chloroform was conducted. The resultingorganic layer was washed with an aqueous sodium hydrogencarbonatesolution and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography (eluting solvent: hexane/ethyl acetate mixed solvent) toobtain 60.4 g (yield: 73.4%) of white crystals of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

[0389]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.96 (1H,d), 3.96 (3H,s)

Reference Example 3

[0390] Production of(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0391] A solution of 10.0 g (47.0 mmoles) of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 100 ml of methanol was cooled to 0° C. Thereto wasgradually added 2.1 g (56.5 mmoles) of sodium borohydride. The mixturewas stirred at room temperature for 2 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein, to obtain 8.3 g (yield: 82.2%) of(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference Example 4

[0392] Production of4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole

[0393] A solution of 8.3 g (38.7 mmoles) of(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolvedin 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.6g (46.4 mmoles) of phosphorus tribromide. The mixture was stirred atroom temperature for 1 hour to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into icewater and extraction with diethyl ether was conducted. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein, to obtain 10.7 g (yield: 99.9%) of4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole.

Reference Example 5

[0394] Production of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol

[0395] 373.8 g (3.0 M) of tert-butylhydrazine hydrochloride and 50 ml ofconcentrated hydrochloric acid were added to a solution of 552.3 g (3.0M) of ethyl trifluoroacetoacetate dissolved in 1,500 ml of ethanol. Themixture was heated and refluxed for 2 days to give rise to a reaction.After the completion of the reaction, the reaction mixture was subjectedto reduced pressure distillation to remove the most part of the solventcontained therein. The residue was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was washed with n-hexane to obtain 369.0g (yield: 59.1%) of a white powder of1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol.

Reference Example 6

[0396] Production of1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0397] 462.0 g (3.0 M) of phosphorus oxychloride was added to 87.7 g(1.2 M) of N,N-dimethylformamide with ice-cooling. Thereto was added, atroom temperature, 208.2 g (1.0 M) of1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol. The mixture was heatedand refluxed for 10 hours to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into waterand extraction with chloroform was conducted. The resulting organiclayer was washed with water, a 5% aqueous sodium hydroxide solution andwater in this order and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (eluting solvent: hexane/ethyl acetate mixedsolvent) to obtain 131.5 g (yield: 21.7%) of white crystals of1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

[0398]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.97 (1H,d), 1.76 (9H,s)

Reference Example 7

[0399] Production of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0400] A solution of 39.9 g (156.9 mmoles) of1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 300 ml of methanol was cooled to 0° C. Thereto wasgradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixturewas stirred at room temperature for 3 hours to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein, to obtain 37.7 g (yield: 93.6%) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

[0401]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 4.60 (2H,d), 1.72 (9H,s), 1.58 (1H,t)

Reference Example 8

[0402] Production of4-bromomethyl-l-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole

[0403] A solution of 9.2 g (35.7 mmoles) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanoldissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto wasadded 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture wasstirred at room temperature overnight to give rise to a reaction. Afterthe completion of the reaction, the reaction mixture was poured into icewater and extraction with diethyl ether was conducted. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein, to obtain 10.0 g (yield: 87.3%) of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyra-zole.

Reference Example 9

[0404] Production of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol

[0405] 43.5 g (136.1 mmoles) of4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole wasadded to 300 ml of a N,N-dimethylformamide solution containing 21.8 g(272.2 mmoles) of sodium hydrosulfide hydrate (purity: 70%). The mixturewas stirred at room temperature overnight to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto ice water and extraction with diethyl ether was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein, to obtain 32.3 g (yield: 87.0%) of(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-metha-nethiol.

[0406]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 3.65 (2H,d), 1.90 (1H, t), 1.70(9H,s)

Reference Example 10

[0407] Production of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine

[0408] 77.5 g (945.0 mmoles) of anhydrous sodium acetate was added, atroom temperature, into a solution of 49.2 g (300.0 mmoles) of4-hydroxy-6-trifluoromethylpyrimidine dissolved in 600 ml of aceticacid. Thereto was gradually added, at 45° C. , 50.3 g (315 mmoles) ofbromine. The mixture was stirred at the same temperature for 3 hours togive rise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was subjected to reduced pressuredistillation to remove the solvent contained therein. The residue waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to reduced pressuredistillation to remove the solvent contained therein. The residue waswashed with n-hexane to obtain 38.9 g (yield: 53.4%) of5-bromo-4-hydroxy-6-trifluoromethylpyrimidine.

Reference Example 11

[0409] Production of 5-bromo-4-chloro-6-trifluoromethylpyrimidine

[0410] 24.3 g (100.0 mmoles) of5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g(120.0 mmoles) of phosphorus oxychloride. The suspension was stirred at100° C. for 2 hours to give rise to a reaction. After confirmation ofthe completion of the reaction, the reaction mixture was graduallypoured into water and extraction with chloroform was conducted. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to reduced pressuredistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography to obtain 21.5 g (yield:82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.

Reference Example 12

[0411] Production of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine

[0412] 0.94 g (13.77 mmoles) of sodium ethoxide was added at roomtemperature into a solution of 3.00 g (11.48 mmoles) of5-bromo-4-chloro-trifluoromethylpyrimidine dissolved in 50 ml ofethanol. The mixture was stirred to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was poured into water and extraction withchloroform was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography to obtain 2.44 g (yield: 82.9%) of5-bromo-4-ethoxy-6-trifluoromethylpyrimidine.

Reference Example 13

[0413] Production of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde

[0414] A solution of 5.76 g (21.3 mmoles) of5-bromo-4-ethoxy-6-trifluoromethylpyrimidine dissolved in 250 ml oftetrahydrofuran was cooled to −78° C. Thereinto was dropwise added 22.6ml of a 1.6 M hexane solution containing 36.1 mM of n-butyl lithium. Themixture was stirred for 40 minutes. Thereto was added 2.7 g (45.1mmoles) of methyl formate. The mixture was stirred for 1.5 hours to giverise to a reaction. After the completion of the reaction, an aqueousammonium chloride solution was added and extraction with ether wasconducted. The resulting organic layer was washed with an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (eluting solvent: hexane/ethyl acetate mixedsolvent) to obtain 3.82 g (yield: 81.6%) of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.

[0415]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 10.41 (1H,s), 8.95 (1H,s), 4.63(2H,q), 1.48 (3H,t)

Reference Example 14

[0416] Production of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol

[0417] A solution of 3.82 g (17.2 mmoles) of4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 mlof methanol was added, with ice-cooling, into a solution of 1.7 g (45.7mmoles) of sodium borohydride dissolved in 50 ml of methanol. Themixture was stirred at 0° C. for 1 hour to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with an aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The resultingsolution was subjected to reduced pressure distillation to remove thesolvent contained therein, to obtain 3.77 g (yield: 97.8%) of(4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol.

[0418]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.80 (1H,s), 4.81 (2H,s), 4.59(2H,q), 2.28 (1H, bR), 1.48 (3H,t)

Reference Example 15

[0419] Production of 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine

[0420] A solution of 3.77 g (17.0 mmoles) of(4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol dissolved in 50 mlof ether was cooled to 0° C. Thereto was added 2.0 g (7.2 mmoles) ofphosphorus tribromide. The mixture was stirred at room temperature for 1hour. The resulting salt was dissolved in methanol and the solution wasstirred for 1 hour to give rise to a reaction. The reaction mixture waspoured into water and extraction with ether was conducted. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein, to obtain a crude product of5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine.

[0421]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 8.79 (1H,s), 4.61 (2H,q), 4.55(2H,s), 1.49 (3H,t)

Reference Example 16

[0422] Production of 1-ethyl-3-trifluoromethyl-1H-pyrazol-5-ol

[0423] Into a solution of 55.2 g (300.0 mmoles) of ethyltrifluoroacetoacetate dissolved in 300 ml of ethanol were added 18.0 g(300.0 mmoles) of monoethylhyrazine and 5 ml of concentratedhydrochloric acid. The mixture was heated and refluxed for 2 days togive rise a reaction. After the completion of the reaction, the reactionmixture was subjected to reduced pressure distillation to remove themost part of the solvent contained therein. The residue was poured intowater and extraction with ethyl acetate was conducted. The resultingorganic layer was washed with water and an aqueous sodium chloridesolution in this order and then dried over anhydrous magnesium sulfate.The resulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was washed withn-hexane to obtain 35.5 g (yield: 65.7%) of a white powder of1-ethyl-3-trifluoromethyl-1H-pyrazol-5-ol.

Reference Example 17

[0424] Production of5-chloro-1-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0425] 91.1 g (591.2 mmoles) of phosphorus oxychloride was added to 18.0g (246.3 mmoles) of N,N-dimethylformamide with ice-cooling. Thereto wasadded, at room temperature, 35.5 g (197.1 mmoles) of1-ethyl-3-trifluoromethyl-1H-pyrazol-5-ol. The mixture was heated andrefluxed for 3 hours to give rise to a reaction. After the completion ofthe reaction, the reaction mixture was poured into water withice-cooling, and extraction with chloroform was conducted. The resultingorganic layer was washed with an aqueous sodium hydrogencarbonatesolution and an aqueous sodium chloride solution in this order and thendried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein. The residue was purified by silica gel columnchromatography to obtain a crude product of5-chloro-l-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

Reference Example 18

[0426] Production of1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0427] 34.3 g (591.3 mmoles) of potassium fluoride (a spray-driedproduct) was added, at room temperature, into a solution of a crudeproduct of5-chloro-l-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde(equivalent to 197.1 mmoles) dissolved in 100 ml of dimethyl sulfoxide.The mixture was stirred at 100 C. for 3 days to give rise to a reaction.After the completion of the reaction, the reaction mixture was pouredinto water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution in this order and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to reduced pressuredistillation to remove the solvent contained therein. The residue waspurified by silica gel column chromatography to obtain 11.1 g (yield:26.8%) of1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

[0428]¹H-NMR [CDCl₃/TMS, δ (ppm)]: 9.86 (1H,d), 4.19 (2H,q), 1.52 (3H,t)

Reference Example 19

[0429] Production of(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0430] A solution of 11.1 g (52.8 mmoles) of1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolvedin 50 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1g (55.5 mmoles) of sodium borohydride. The mixture was stirred at roomtemperature for 3 hours to give rise to a reaction. After the completionof the reaction, the reaction mixture was poured into water andextraction with diethyl ether was conducted. The resulting organic layerwas washed with an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected toreduced pressure distillation to remove the solvent contained therein,to obtain 9.1 g (yield: 81.3%) of(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference Example 20

[0431] Production of4-bromomethyl-1-ethyl-5-fluoro-3-trifluoromethyl-lh-pyrazole

[0432] A solution of 9.1 g (42.9 mmoles) of(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolvedin 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.2g (45.0 mmoles) of phosphorus tribromide. The mixture was stirred atroom temperature overnight to give rise to a reaction. After thecompletion of the reaction, the reaction mixture was poured into icewater and extraction with diethyl ether was conducted. The resultingorganic layer was washed with an aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The resulting solution wassubjected to reduced pressure distillation to remove the solventcontained therein, to obtain a crude product of4-bromomethyl-1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole.

Reference Example 21

[0433] Production of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde

[0434] 42.0 g (711.9 mmoles) of potassium fluoride was added into asolution of 60.4 g (282.7 mmoles) of5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at120 to 140° C. for 5 hours to give rise to a reaction. Afterconfirmation of the completion of the reaction, the reaction mixture waspoured into water and extraction with ethyl acetate was conducted. Theresulting organic layer was washed with water and an aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Theresulting solution was subjected to reduced pressure distillation toremove the solvent contained therein. The residue was purified by silicagel column chromatography (developing solvent: hexane/ethyl acetatemixed solvent) to obtain 36.8 g (yield: 66.0%) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-.

Reference Example 22

[0435] Production of(5-fluoro-l-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol

[0436] A solution of 36.8 g (187.6 mmoles) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 200 ml of methanol was added, with ice-cooling, into asolution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500ml of methanol. The mixture was stirred at 0° C. for 30 minutes to giverise to a reaction. After confirmation of the completion of thereaction, the reaction mixture was poured into water and extraction withethyl acetate was conducted. The resulting organic layer was washed withwater and an aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The resulting solution was subjected toreduced pressure distillation to remove the solvent contained therein,to obtain 35.4 g (yield: 95.4%) of(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference Example 23

[0437] Production of4-bromomethyl-5-fluoro-l-methyl-3-trifluoromethyl-1H-pyrazole

[0438] A solution of 35.4 g (178.7 mmoles) of5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehydedissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto wasadded 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture wasstirred at room temperature for 12 hours to give rise to a reaction.After confirmation of the completion of the reaction, the reactionmixture was poured into water and extraction with diethyl ether wasconducted. The resulting organic layer was washed with water and anaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The resulting solution was subjected to reduced pressuredistillation to remove the solvent contained therein, to obtain 31.4 g(yield: 80.8%) of4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.

[0439] The herbicide of the present invention contains, as an activeingredient, an isoxazoline derivative represented by the general formula[I].

[0440] In using the compound of the present invention as a herbicide,the present compound may be used by itself. It can also be used in theform of a powder, a wettable powder, an emulsion, a flowable agent, finegranules, granules, etc. by mixing with a carrier, a surfactant, adispersing agent, an auxiliary agent, etc. all generally used inherbicide production.

[0441] As the carrier used in herbicide production, there can bementioned, for example, solid carriers such as talc, bentonite, clay,kaolin, diatomaceous earth, white carbon, vermiculite, calciumcarbonate, slaked lime, siliceous sand, ammonium sulfate, urea and thelike; and liquid carriers such as isopropyl alcohol, xylene,cyclohexane, methylnaphthalene and the like.

[0442] As the surfactant and the dispersing agent, there can bementioned, for example, metal salts of alkylbenzenesulfonic acids, metalsalts of dinaphthylmethanedisulfonic acid, salts of alcohol sulfates,alkylarylsulfonic acid salts, ligninsulfonic acid salts, polyoxyethyleneglycol ether, polyoxyethylene alkyl aryl ethers, monoalkylates ofpolyoxyethylene sorbitan and the like. As the auxiliary agent, there canbe mentioned, for example, carboxymethyl cellulose, polyethylene glycoland gum arabic. The present herbicide, when used, is diluted to anappropriate concentration and sprayed or applied directly.

[0443] The herbicide of the present invention can be used bypost-emergence application, pre-emergence application or water surfaceapplication, etc. The amount of the active ingredient used is determinedappropriately so as to meet the application purpose. When the presentcompound is made into a powder or granules, the amount is appropriatelydetermined in a range of 0.01 to 10% by weight, preferably 0.05 to 5% byweight. When the present compound is made into an emulsion or a wettablepowder, the amount is appropriately determined in a range of 1 to 50% byweight, preferably 5 to 30% by weight. When the present compound is madeinto a flowable agent, the amount is appropriately determined in a rangeof 1 to 40% by weight, preferably 5 to 30% by weight.

[0444] The amount of the present herbicide used varies depending uponthe kind of the compound used, the target weed, the tendency of weedemergence, the environmental conditions, the form of the herbicide used,etc. When the present herbicide is used per se as in the case of apowder or granules, the amount is appropriately selected in a range of 1g to 50 kg, preferably 10 g to 10 kg per 1 hectare in terms of theactive ingredient. When the present herbicide is used in a liquid formas in the case of an emulsion, a wettable powder or a flowable agent,the amount is appropriately selected in a range of 0.1 to 50,000 ppm,preferably 10 to 10,000 ppm.

[0445] The compound of the present invention may be mixed as necessarywith an insecticide, a fungicide, other herbicide, a plantgrowth-regulating agent, a fertilizer, etc.

[0446] Next, herbicide formulation from the present compound isdescribed specifically by showing typical examples of herbicideformulation. The kinds of compounds and additives and their compoundingratios are not restricted to those shown below and can be varied widely.In the following description, “parts” refer to parts by weight.

FORMULATION 1 Wettable Powder

[0447] 10 parts of a present invention compound No. 2 were mixed with0.5 part of polyoxyethylene octylphenyl ether, 0.5 part of a sodium saltof a β-naphthalenesulfonic acid-formalin condensate, 20 parts ofdiatomaceous earth and 69 parts of clay. The mixture was ground toobtain a wettable powder.

FORMULATION 2 Flowable Agent

[0448] 20 parts of a coarsely ground present invention compound No. 2were dispersed in 69 parts of water. Thereto were added 4 parts of asulfate of a polyoxyethylene styrenated phenyl ether, 7 parts ofethylene glycol and 200 ppm, relative to the herbicide produced, ofSilicone AF-118N (a product of Asahi Chemical Industry, Co. Ltd.). Theresulting mixture was stirred for 30 minutes using a high-speed stirrerand then ground using a wet grinder to obtain a flowable agent.

FORMULATION 3 Emulsion

[0449] To 30 parts of a present invention compound No. 2 were added 60parts of an equal volume mixture of xylene and isophorone and 10 partsof a surfactant mixture of a polyoxyethylene sorbitan alkylate, apolyoxyethylene alkylaryl polymer and an alkylaryl sulfonate. Theresulting mixture was stirred sufficiently to obtain an emulsion.

FORMULATION 4 Granules

[0450] 10 parts of water was added to 10 parts of a present inventioncompound No. 2, 80 parts of an extender which was a 1:3 mixture of talcand bentonite, 5 parts of white carbon and 5 parts of a surfactantmixture of a polyoxyethylene sorbitan alkylate, a polyoxyethylenealkylaryl polymer and an alkylaryl sulfonate. The resulting mixture waskneaded sufficiently to form a paste. The paste was extruded through theeyes (diameter: 0.7 mm) of a sieve. The extrudate was dried and cut intoa length of 0.5 to 1 mm to obtain granules.

[0451] Next, Application Examples of the present herbicide are describedto show the effect of the present compound.

Application Example 1 Test For Herbicidal Effect By Paddy FieldPre-Emergence Treatment

[0452] A paddy field soil was filled in a plastic pot of 100 cm² andsubjected to puddling. Then, seeds of Echinochloa oryzicola Vasing. andMonochoria vaginalis (Murm. f.) Presl var. plantaginea (Roxb.)Solms-Laub. were sowed and water was filled in a depth of 3 cm. Nextday, wettable powders produced in accordance with the Formulation 1 werediluted with water and dropped on the water surface. The applicationamount of each wettable powder was 1,000 g per 1 hectare in terms of theactive ingredient. Then, breeding was made in a greenhouse, and theherbicidal effect of each wettable powder was examined at the 21st dayfrom the treatment in accordance with the standard shown in Table 61.The results are shown in Table 62. TABLE 61 Herbicidal effect (extent ofgrowth inhibition) and Index phytotoxicity 5 A herbicidal effect orphytotoxicity of 90% or more 4 A herbicidal effect or phytotoxicity of70% to less than 90% 3 A herbicidal effect or phytotoxicity of 50% toless than 70% 2 A herbicidal effect or phytotoxicity of 30% to less than50% 1 A herbicidal effect or phytotoxicity of 10% to less than 30% 0 Aherbicidal effect or phytotoxicity of 0% to less than 10%

[0453] TABLE 62 Monochoria vaginalis Active Echinochloa (Burm. f) Preslingredient oryzicola Var. plantaginea Comp. No (g/ha) Vasing (Roxb.)Solms-Laub. 2 1000 5 5

Application Example 2 Test For Herbicidal Effect By Upland FieldPre-Emergence Treatment

[0454] An upland field soil was filled in a plastic pot of 80 cm². Seedsof Echinochloa crus-galli (L.) Beauv. var. crus-galli and Setariaviridis (L.) Beauv. were sowed, followed by covering with the same soil.Wettable powders produced in accordance with the Formulation 1 werediluted with water and sprayed uniformly on the soil surface using asmall sprayer, in an amount of 1,000 liters per 1 hectare so that theamount of each active ingredient became 1,000 g per 1 hectare. Then,breeding was made in a greenhouse, and the herbicidal effect of eachwettable powder was examined at the 21st day from the treatment inaccordance with the standard shown in Table 61. The results are shown inTable 63. TABLE 63 Active Echinochloa crus-galli Setaria viridis Comp.ingredient (L.) Beauv. Var. (L.) No (g/ha) crus-galli Beauv. 2 1000 5 5

Application Example 3 Test For Herbicidal Effect By Upland FoliageTreatment

[0455] A sand was filled in a plastic pot of 80 cm². Seeds ofEchinochloa crus-galli (L.) Beauv. var. crus-galli and Setaria viridis(L.) Beauv. were sowed. Breeding was made in a greenhouse for 2 weeks.Wettable powders produced in accordance with the Formulation 1 werediluted with water and sprayed on the whole foliage of plants from abovethe plants using a small sprayer in an amount of 1,000 liters per 1hectare so that the amount of each active ingredient became 1,000 g per1 hectare. Then, breeding was made in the greenhouse, and the herbicidaleffect of each wettable powder was examined at the 14th day from thetreatment in accordance with the standard shown in Table 61. The resultsare shown in Table 64. TABLE 64 Active Echinochloa crus-galli Setariaviridis Comp. ingredient (L.) Beauv. Var. (L.) No (g/ha) crus-galliBeauv. 40 1000 5 5

INDUSTRIAL APPLICABILITY

[0456] The compound represented by the general formula [I] according tothe present invention shows an excellent herbicidal effect over a wideperiod from before germination to growth, to various weeds causingproblems in upland fields, for example, broadleaf weeds [e.g. Polygonumlapathifolium L. subsp. nodosum (Pers.) Kitam., Amaranthus viridis L.,Chenopodium album L., Stellaria media (L.) Villars, Abutilon theophrastiMedik., Sida spinosa, Sesbaria exaltata, Ipomoea spp. and Xanthiumstrumarium L.], perennial or annual cyperaceous weeds [e.g. Cyperusrotundus L., Cyperus esculentus, Kyllinga brevifolia Rottb. subsp.leiolepis (Fraxch. et Savat.) T. Koyama, Cyperus microiria Steud., andCyperus iria L.], and Granineous weeds [e.g. Echinochloa crus-galli (L.)Beauv. var. crus-galli, Digitaria ciliaris (Retz.) Koeler, Setariaviridis (L.) Beauv., Poa annua L., Sorghum halepense (L.) Pers.,Alopecurus aequalis Sobol. var. amurensis (Komar.) Ohwi, and Avena fatuaL.]. Further, the present compound shows a herbicidal effect also toweeds emerging in paddy fields, i.e. annual weeds [e.g. Echinochloaoryzicola Vasing., Cyperus difformis L., and Monochoria vaginalis (Burm.f.) Presl. var. plantaginea (Roxb.) Solms-Laub.] and perennial weeds[e.g. Sagittaria trifolia L., Sagittaria pygmaea Miq., Cyperus serotinusRottb., Eleocharis kuroguwai Ohwi, Scirpus juncoides Roxb. subsp.hotarui (Ohwi) T. Koyama and Alisma canaliculatum].

[0457] The herbicide of the present invention has high safety to crops,particularly to rice, wheat, barley, corn, grain sorghum, soybean,cotton, sugar beat, etc.

1. An isoxazoline derivative having the following general formula [I]and a pharmaceutically acceptable salt thereof:

wherein R¹ is a C1 to C4 haloalkyl group; R² is a hydrogen atom, a C1 toC10 alkyl group, a C1 to C4 haloalkyl group, a C3 to C8 cycloalkylgroup, or a C3 to C8 cycloalkyl C1 to C3 alkyl group; R³ and R⁴ may bethe same or different and are each a hydrogen atom, a C1 to C10 alkylgroup or a C3 to C8 cycloalkyl group; or R³ and R⁴ may be bonded to eachother to form a C3 to C7 spiro ring together with the carbon atom towhich they bond; or R² and R³ may be bonded to each other to form a 5-to 8-membered ring together with the carbon atoms to which they bond; R⁵and R⁶ may be the same or different and are each a hydrogen atom or a C1to C10 alkyl group; Y is a pyrrolyl group, a pyrazolyl group, anisothiazolyl group, an oxazolyl group, an imidazolyl group, apyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinylgroup, a triazolyl group, an oxadiazolyl group, a benzothienyl group, anindolyl group, a benzoxazolyl group, a benzoimidazolyl group, abenzoisoxazolyl group, a benzoisothiazolyl group, an indazolyl group, aquinolyl group, an isoquinolyl group, a phthalazinyl group, aquinoxalinyl group, a quinazolinyl group, a cinnolinyl group or abenzotriazolyl group (in these heterocyclic groups, when the hetero atomis a nitrogen atom, the nitrogen atom may be oxidized to form anN-oxide); these heterocyclic groups may each be substituted with one tosix same or different groups selected from the following substituentgroup α (when the heterocyclic group is substituted at the two adjacentpositions with two alkyl groups, two alkoxy groups, an alkyl group andan alkoxy group, an alkyl group and an alkylthio group, an alkyl groupand an alkylsulfonyl group, an alkyl group and a monoalkylamino group,or an alkyl group and a dialkylamino group, the two groups may form a 5-to 8-membered ring which may be substituted with 1 to 4 halogen atoms);n is an integer of 0 to
 2. [Substituent group a] Hydroxyl group; halogenatoms; C1 to C10 alkyl groups; CI to CI0 alkyl groups eachmono-substituted with a group selected from the following substituentgroup β, C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 toC10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with agroup selected from the following substituent group γ; C1 to C4haloalkoxy groups; C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1to C3 alkyloxy groups; C1 to C10 alkylthio groups; C1 to C10 alkylthiogroups each mono-substituted with a group selected from the substituentgroup γ; C1 to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 toC6 alkenyloxy groups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxygroups; C1 to C10 alkylsulfinyl groups; C1 to C10 alkylsulfonyl groups;C1 to C10 alkylsulfonyl groups each mono-substituted with a groupselected from the substituent group γ; C1 to C4 haloalkylsulfinylgroups; C1 to C4 haloalkylsulfonyl groups; C1 to C10 alkylsulfonyloxygroups; C1 to C4 haloalkylsulfonyloxy groups; optionally substitutedphenyl group; optionally substituted phenoxy group; optionallysubstituted phenylthio group; optionally substituted aromaticheterocyclic groups; optionally substituted aromatic heterocyclic oxygroups; optionally substituted aromatic heterocyclic thio groups;optionally substituted phenylsulfinyl groups; optionally substitutedphenylsulfonyl groups; optionally substituted aromatic heterocyclicsulfinyl groups; optionally substituted aromatic heterocyclic sulfonylgroups; optionally substituted phenylsulfonyloxy groups; C1 to C6 acylgroups; C1 to C4 haloalkylcarbonyl groups; optionally substitutedbenzylcarbonyl group; optionally substituted benzoyl group; carboxylgroup; C1 to C10 alkoxycarbonyl groups; optionally substitutedbenzyloxycarbonyl group; optionally substituted phenoxycarbonyl group;cyano group; carbamoyl group (its nitrogen atom may be substituted withsame or different groups selected from C1 to C10 alkyl groups andoptionally substituted phenyl group); C1 to C6 acyloxy groups; C1 to C4haloalkylcarbonyloxy groups; optionally substituted benzylcarbonyloxygroup; optionally substituted benzoyloxy group; nitro group; and aminogroup (its nitrogen atom may be substituted with same or differentgroups selected from C1 to C10 alkyl groups, optionally substltutedphenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups,optionally substituted benzyl carbonyl group, optionally substitutedbenzoyl group, C1 to C10 alkylsulfonyl group, C1 to C4 haloalkylsulfonylgroups, optionally substituted benzylsulfonyl group, and optionallysubstituted phenylsulfonyl group). [Substituent group β] Hydroxyl group;C3 to C8 cycloalkyl groups (which may be substituted with halogen atomsor C1 to C10 atkyl groups); C1 to C10 alkoxy groups; CI to CI0 alkylthiogroups; C1 to C 10 alkylsulfonyl groups; C1 to C10 alkoxycarbonylgroups; C2 to C6 haloalkenyl groups; amino group (its nitrogeh atom maybe substituted with same or different groups selected from C1 to C10alkyl groups, C2 to C6 acyl groups; C1 to C4 haloalkylcarbonyl groups,C1 to C10 alkylsulfonyl groups and C1 to C4 haloalkylsulfonyl groups);carbamoyl group (its nitrogen atom may be substituted with same ordifferent groups selected from C1 to C10 alkyl groups and optionallysubstituted phenyl group); C2 to C6 acyl groups; C1 to C4haloalkylcarbonyl groups; C1 to C10 alkoxyimino groups; cyano group;optionally substituted phenyl group; and optionally substituted phenoxygroup. [Substituent group γy] C1 to C10 alkoxycarbonyl groups;optionally substituted phenyl group; optionally substituted aromaticheterocyclic groups; cyano group; and carbamoyl group (its nitrogen atommay be substituted with same or different C1 to C10 alkyl groups).
 2. Anisoxazoline derivative or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein the substituent group a is represented byhydroxyl group; halogen atoms; C1 to C10 alkyl groups; C1 to C10 alkylgroups each mono-substituted with a group selected from the substituentgroup β; C1 to C4 haloalkyl groups; C3 to C8 cycloalkyl groups; C1 toC10 alkoxy groups; C1 to C10 alkoxy groups each mono-substituted with agroup selected from the substituent group γ; C1 to C4 haloalkoxy groups;C3 to C8 cycloalkyloxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxygroups; C1 to C10 alkylthio groups; C1 to C10 alkylthio groups eachmono-substituted with a group selected from the substituent group γ; C1to C4 haloalkylthio groups; C2 to C6 alkenyl groups; C2 to C6 alkenyloxygroups; C2 to C6 alkynyl groups; C2 to C6 alkynyloxy groups; C1 to C10alkylsulfonyl groups; C1 to C4 haloalkylsulfonyl groups; optionallysubstituted phenyl group; optionally substituted phenoxy group;optionally substituted phenylthio group; optionally substituted aromaticheterocyclic groups; optionally substituted aromatic heterocyclic oxygroups; optionally substituted aromatic heterocyclic thio groups;optionally substituted phenylsulfonyl groups; optionally substitutedaromatic heterocyclic sulfonyl groups; C1 to C6 acyl groups; C1 to C4haloalkylcarbonyl groups; optionally substituted benzylcarbonyl group;optionally substituted benzoyl group; carboxyl group; C1 to C10alkoxycarbonyl groups; cyano group; carbamoyl group (its nitrogen atommay be substituted with same or different groups selected from C1 to C10alkyl groups and optionally substituted phenyl group); nitro group; andamino group (its nitrogen atom may be substituted with same or differentgroups selected from C1 to C10 alkyl groups, optionally substitutedphenyl group, C1 to C6 acyl groups, C1 to C4 haloalkylcarbonyl groups,optionally substituted benzylcarbonyl group, optionally substitutedbenzoyl group, C1 to C10 alkylsulfonyl groups, C1 to C4haloalkylsulfonyl groups, optionally substi tuted benzylsulfonyl group,and optionally substituted phenylsulfonyl group).
 3. An isoxazolinederivative or a pharmaceutically acceptable salt thereof according toclaim 2, wherein the substituent group a is represented by halogenatoms; C1 to C10 alkyl groups; C1 to C4 haloalkyl groups; C1 to C10alkoxy C1 to C3 alkyl groups; C3 to C8 cycloalkyl groups (which may besubstituted with halogen atom or alkyl group); C1 to C10 alkoxy groups;C1 to C4 haloalkoxy groups; C3 to C8 cycloalkyl C1 to C3 alkyloxygroups; optionally substituted phenoxy group; C1 to C10 alkylthiogroups; C1 to C10 alkylsulfonyl groups; acyl groups; C1 to C4haloalkylcarbonyl groups; C1 to C10 alkoxycarbonyl groups; cyano groupand carbamoyl group (its nitrogen atom may be substituted with same ordifferent C1 to C10 alkyl groups).
 4. An isoxazoline derivative or apharmaceutically acceptable salt thereof according to claim 1, whereinR¹ is a chloromethyl group; R² is a methyl group or an ethyl group; R³,R⁴, R⁵ and R⁶ are each a hydrogen atom.
 5. An isoxazoline derivative ora pharmaceutically acceptable salt thereof according to claim 1, whereinY is a pyrrolyl group, a pyrazolyl group, an isothiazolyl group, anoxazolyl group, an imidazolyl group, a pyridazinyl group, a pyrimidinylgroup, a pyrazinyl group, a triazinyl group, a triazolyl group or anoxadiazolyl group.
 6. An isoxazoline derivative or a pharmaceuticallyacceptable salt thereof according to claim 5, wherein Y is a pyrazolylgroup or a pyrimidinyl group.
 7. An isoxazoline derivative or apharmaceutically acceptable salt thereof according to claim 6, wherein Yis a pyrazol-4-yl group or a pyrimidin-5-yl group.
 8. An isoxazolinederivative or a pharmaceutically acceptable salt thereof according toclaim 7, wherein Y is a pyrazol-4-yl group and the pyrazole ring issubstituted at the 3- and 5-positions with a group selected from thesubstituent group α and at the 1-position with a hydrogen atom, a C1 toC10 alkyl group, a C1 to C10 alkyl group mono-substituted with a groupselected from the substituent group β, a C1 to C4 haloalkyl group, a C3to C8 cycloalkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynylgroup, a C1 to C10 alkylsulfinyl group, a C1 to C10 alkylsulfonyl group,a C1 to C10 alkylsulfonyl group mono-substituted with a group selectedfrom the substituent group γ, a C1 to C4 haloalkylsulfonyl group, anoptionally substituted phenyl group, an optionally substituted aromaticheterocyclic group, an optionally substituted phenylsulfonyl group, anoptionally substituted aromatic heterocyclic sulfonyl group, an acylgroup, a C1 to C4 haloalkylcarbonyl group, an optionally substitutedbenzylcarbonyl group, an optionally substituted benzoyl group, a C1 toC10 alkoxycarbonyl group, an optionally substituted benzyloxycarbonylgroup, an optionally substituted phenoxycarbonyl group, a carbamoylgroup (its nitrogen atom may be substituted with same or differentgroups selected from C1 to C10 alkyl groups and optionally substitutedphenyl group), or an amino group (its nitrogen atom may be substitutedwith same or different groups selected from C1 to C10 alkyl groups,optionally substituted phenyl group, acyl groups, C1 to C4haloalkylcarbonyl groups, optionally substituted benzylcarbonyl group,optionally substituted benzoyl group, C1 to C10 alkylsulfonyl groups, C1to C4 haloalkylsulfonyl groups, optionally substituted benzylsulfonylgroup and optionally substituted phenylsulfonyl group).
 9. Anisoxazoline derivative or a pharmaceutically acceptable salt thereofaccording to claim 7, wherein Y is a pyrimidin-5-yl group and thepyrimidine ring are substituted with a group selected from thesubstituent group α, at the 4- and 6-positions.
 10. A herbicidecontaining, as an active ingredient, an isoxazoline derivative or apharmaceutically acceptable salt thereof according to claim 1.